WO2019155337A1

WO2019155337A1 - Compositions comprising a cannabinoid and punicalagin and methods of use thereof

Info

Publication number: WO2019155337A1
Application number: PCT/IB2019/050854
Authority: WO
Inventors: Zohar KOREN
Original assignee: Scicann Therapeutics Inc.; Dr. Mark Friedman Ltd.
Priority date: 2018-02-06
Filing date: 2019-02-04
Publication date: 2019-08-15

Abstract

Provided herein are compositions comprising therapeutically effective amounts of at least one cannabinoid and of punicalagin, as essentially pure isolates or synthetic or as components of essential oils or plant extracts or combinations thereof. The combination compositions comprising punicalagin and cannabidiol (CBD) exhibit a strong synergistic effect in the reduction of the local aorta pro-inflammatory IL-6 cytokine levels. This result demonstrates the potential superior and synergistic therapeutic efficacy that can be achieved by using these active agents as a combined atherosclerosis therapy as compared to each of them separately. The pharmaceutical compositions of this invention are useful for the treatment of inflammation in atherosclerotic plaques, thus rendering them less vulnerable to erupt and clog small blood vessels in the heart or brain, atherosclerosis or blood vessel calcification and reducing Reactive Oxygen Species (ROS) presence and reactive oxidative stress in atherosclerotic lesions, thus preventing further damage to vessel tissue and accumulation of debris, calcium, inflammatory agents and cells in lesions.

Description

COMPOSITIONS COMPRISING A CANNABINOID AND PUNICALAGIN

AND METHODS OF USE THEREOF

Cross Reference to Related Applications

This application claims priority to U.S. Provisional Patent Application Serial No. 62/626,751 filed 6-Feb-20l8, the entire contents of which are hereby incorporated by reference in their entirety.

Field of the Invention

The present invention, in some embodiments thereof, relates to fixed dose combination (FDC) compositions, more particularly, but not exclusively, to compositions comprising at least one cannabinoid and punicalagin and methods of use thereof.

Background

Cannabis, more commonly known as marijuana, is a genus of flowering plants that includes at least three species, Cannabis sativa, Cannabis indica, and Cannabis ruderalis as determined by plant phenotypes and secondary metabolite profiles.

Punicalagin is obtained from one or more species of the genus Lythraceae, said species being selected from Punica granatum, P. protopunica and all the P. granatum cultivars, and one or more species of genus Myrtales, said species being selected from Terminalia catappa, Terminalia myriocarpa and Combretum mode.

Punicalagins are large molecules (ellagitannins) found mostly in Pomegranates and Pomegranate Juice. They are very potent anti-oxidants, and can be metabolized into other compounds (ellagic acid, urolithins) that themselves have anti-oxidant capabilities (although lesser). This large anti-oxidant value of punicalagins, about thrice that of red wine and green tea, is what brought Pomegranates to fame.

Summary of the Invention

The present invention provides fixed dose combination compositions (FDC), more specifically, compositions comprising at least one cannabinoid in essentially pure form or as a component of a cannabis plant extract or essential oil and punicalagin in essentially pure form or as a component of a plant extract or essential oil or combinations thereof. Also provided are methods of treatment of a number of diseases by administration to a patient in need thereof therapeutically effective amounts of the above combination compositions.

In some embodiments, there is provided a combination composition comprising a therapeutically effective amount of at least one cannabinoid and a therapeutically effective amount of punicalagin.

In some other embodiments, there is provided the composition of this invention, wherein the at least one cannabinoid and the punicalagin, whether plant isolate or synthetic, are essentially pure, having an assay of at least 92% w/w, at least 95% w/w or at least 98% w/w.

In some embodiments, there is provided the composition of this invention, wherein the at least one cannabinoid is a component of a cannabis essential oil or extract and punicalagin is a component of a punicalagin-containing essential oil or extract.

According to some embodiments, there is provided the FDC composition of this invention, wherein the at least one cannabinoid is a plant isolate or synthetic, is essentially pure having an assay of at least 92% w/w, at least 95% w/w or at least 98% w/w and punicalagin is a component of a punicalagin-containing plant extract or essential oil.

In some embodiments, there is provided the composition of this invention, wherein the at least one cannabinoid is a component of a cannabis essential oil or extract and punicalagin is an essentially pure plant isolate or essentially pure synthetic punicalagin.

According to some embodiments, there is provided the composition of this invention, wherein it is a pharmaceutical composition for use as anti-allergic, anti-inflammatory, immunomodulator, antioxidant, anti-microbial, antibacterial, antifungal, antiviral, antinociceptive, analgesic, anesthetic, anti-cancer, apoptosis inducing, antiscorbutic, antipyretic, anti-malarial, addiction mitigatory, anxiolytic, anti-depressant, diuretic, anti-diarrheal, vasodilator or aphrodisiac.

In some other embodiments, there is provided the composition of this invention, wherein it is a cosmeceutical or nu tricosmetic, for alleviating, treatment, curing, mitigating or preventing a dermatological disease or condition selected from acne, emption, burns, and cuts.

In some embodiments, there is provided the composition of this invention, wherein formulated as two or more units of pharmaceutical dosage forms, at least one of which comprises essentially pure punicalagin, a punicalagin-containing extract or a punicalagin-containing essential oil, and at least one dosage form comprises at least one essentially pure cannabinoid or cannabis plant extract or cannabis plant essential oil. According to some embodiments, there is provided the composition of this invention, wherein the at least one cannabinoid is selected from CBD, its isomers, derivatives and mixtures thereof.

According to some other embodiments, there is provided the composition of this invention wherein the at least one cannabinoid is selected from THC, its isomers, derivatives and mixtures thereof.

In some embodiments, there is provided a method for treating, curing, mitigating or alleviating a disease, disorder or medical condition, comprising co-administering to a subject in need thereof a therapeutically effective amount of punicalagin in the form of essentially pure punicalagin, or a punicalagin plant isolate, or a punicalagin-containing plant extract or essential oil, and a therapeutically effective amount of at least one essentially pure cannabinoid, a cannabis plant extract, or a cannabis plant essential oil, thereby treating, curing, mitigating or alleviating the disease, disorder or medical condition..

In some embodiments, there is provided the method of this invention, wherein the disease, disorder or medical condition is selected from a cardiovascular disease, atherosclerosis, a gastro- enterologic disease, inflammation, an autoimmune disease, an immunodeficiency disease, a neurodegenerative disease, neuronal damage, neuro -inflammation, an oncologic disease, a mental or psychiatric disease, a skin disease, viral, bacterial or fungal infection, and blood vessels diseases or disorders.

In some embodiments, there is provided the method of this invention, wherein the disease, disorder or medical condition is selected from cancer, prostate cancer, nausea, appetite loss and pain associated with cancer and chemotherapy; nausea, appetite loss, pain and wasting associated with AIDS; toothache; arthritis and rheumatism; glaucoma; migraine; scurvy; muscle spasticity; alcohol and narcotics withdrawal; stress; asthma; Tourette syndrome, Cervical dystonia; epileptic seizures; dementia; dysmenorrhea; anxiety disorders; depression; diabetes, diabetes-related retinopathy; diarrhea; neuropathic pain; chronic pain; psoriasis; dermatitis; swimmer’s eczema; Alzheimer’s disease; Huntington disease; Parkinson; Lyme disease; malaria; vasoconstriction, allergy; edema; liver inflammation; schizophrenia; colitis; painful spasms; fibromyalgia; sexual disfunction; post- traumatic stress disorder (PTSD); sepsis; necrotizing soft tissue infections (NSTI); acute or chronic pancreatitis; opioid addiction; inflammatory bowel disease (IBD); non-alcoholic fatty liver disease (NAFLD); non-alcoholic fatty liver disease (NAFLD); and irritable bowel syndrome (IBS). In some embodiments, there is provided the method of this invention, wherein the disease, disorder or medical condition is atherosclerosis and said method is beneficial for reducing inflammation in atherosclerotic plaques, thus rendering them less vulnerable to empt and clog small blood vessels in the heart or brain.

In some embodiments, there is provided the method of this invention, wherein the disease, disorder or medical condition is atherosclerosis or blood vessel calcification and said method is beneficial for reducing Reactive Oxygen Species (ROS) presence and reactive oxidative stress in atherosclerotic lesions, thus preventing further damage to vessel tissue and accumulation of debris, calcium, inflammatory agents and cells in lesions.

In some embodiments, there is provided the method of this invention, wherein the disease, disorder or medical condition is cerebral infarction or stroke and said method is beneficial in reducing infarct size and increasing blood flow.

In some other embodiments, there is provided the method of this invention, wherein the disease, disorder or medical condition is caused by inflammation or an inflammatory process, selected from Alzheimer's disease, ankylosing spondylitis, arthritis (osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis, asthma, atherosclerosis, Crohn's disease, Colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus erythematosus (SLE), nephritis, Parkinson's disease and ulcerative colitis.

In some embodiments, there is provided the method of this invention, wherein the disease, disorder or medical condition is myocardial, liver or renal ischemic /reperfusion injury and the method is beneficial by providing protection.

In some embodiments, there is provided the method of this invention, wherein the disease, disorder or medical condition is an autoimmune disease.

In one embodiment, the autoimmune disease is autoimmune hepatitis.

In some other embodiments, there is provided the method of this invention, wherein co administration of and at least one cannabinoid and punicalagin or punicalagin-containing plant extract or essential oil results in a therapeutic effect selected from a synergistic effect, an additive effect, a potentiating effect and any combination thereof.

In some embodiments, there is provided the method of this invention, wherein the composition comprising at least one cannabinoid and punicalagin exhibits a synergistic therapeutic effect with respect to the therapeutic effect of the at least one cannabinoid and of punicalagin respectively, administered separately in a similar amount. In some other embodiments, there is provided the method of this invention, wherein the at least one cannabinoid is selected from CBD, its isomers, derivatives and mixtures thereof.

According to some embodiments, there is provided the method of this invention, wherein the at least one cannabinoid is selected from THC, its isomers, derivatives and mixtures thereof..

In some embodiments, the pharmaceutical composition is an analgesic agent.

In some embodiments, the pharmaceutical composition is an anti-cancer agent.

In some embodiments, the disease, disorder or medical condition that is treatable, curable, mitigated or alleviated is selected from a gastro-enterologic disease, inflammation, an autoimmune disease, an immunodeficiency disease, a neurodegenerative disease, an oncologic disease, a cardiovascular disease, a mental or psychiatric disease, a skin disease, viral, bacterial or fungal infection, and blood vessels diseases or disorders.

In some embodiments, co-administration of punicalagin or punicalagin-containing plant extract and at least one cannabinoid results in a therapeutic effect selected from a synergistic effect, an additive effect, a potentiating effect and any combination thereof.

Brief Description of the Drawings

Fig. 1 depicts the local aorta pro-inflammatory IL-6 cytokine levels (pg/nl) after treatment with CBD, punicalagin and CBD + punicalagin vs. vehicle and healthy animals

Fig. 2 depicts the synergistic efficacy of CBD + punicalagin vs. CBD and punicalagin as single drugs in the reduction of local aorta pro-inflammatory IL-6 cytokine levels

Detailed Description of the Invention

The present invention provides combination compositions comprising therapeutically effective amounts of at least one cannabinoid and punicalagin.

In some embodiments, the compositions comprise at least one cannabinoid and punicalagin or punicalagin-containing plant extract whether as isolates from a plant source or synthetic, being essentially pure and having an assay of at least 95%, preferably at least 98%.

In some other embodiments, the at least one cannabinoid in the composition is cannabidiol

(CBD).

The essentially pure isolates and synthetic cannabinoids and punicalagin have some advantages over the respective plant extracts or essential oils. 1. The essentially pure isolates and synthetic cannabinoids and punicalagin are essentially free of impurities, the nature and percentage of which are somewhat unpredictable as they depend on the plant source, seasonal factors, extraction process, etc.

2. Some of the cannabis plant extract impurities may have a hallucinogenic affect, which is undesirable in a dmg.

3. Solid cannabinoids or punicalagin are easier to formulate than oils.

A plant isolate is an active agent, in this case a cannabinoid or punicalagin, isolated from a botanical source (a plant) and subsequently purified.

Just as an example, CBD (one of the important cannabinoids of this invention), is available as a CBD isolate.

CBD isolate is all-natural cannabidiol in its purest form. The CBD compounds found in hemp oil are isolated and then refined down to high purity to eliminate oils, plant material, waxes, chlorophyll, and more. CBD isolate is typically offered in a fine white powder containing 99% pure cannabidiol.

The isolate gives patients complete control of exactly how much CBD goes into each serving. Because CBD isolate is over 99% pure, each milligram of CBD isolate represents a milligram of active CBD.

Some cannabinoids may be obtained by chemical synthesis. The synthesis of CBD has been accomplished by several research groups: "Synthese und Chiralitat des (-)-Cannabidiols". Helv. Chim. Acta. 50 (2): 719-723, Gaoni Y, Mechoulam R (1985). "Boron trifluoride etherate on alumina - a modified Lewis acid reagent. An improved synthesis of cannabidiol". Tetrahedron Letters. 26 (8): 1083-1086.

Relatively pure punicalagin isolates as well as extracts from a number of plants (vide infra) and plant parts are commercially available from a number of sources. Pharmaceutical use may require further purification.

Punicalagin is commercially available as an essentially pure compound from several vendors, up to 98% purity.

Punicalagin is extracted for example from the Pomegranate husk and is commercially available from Stanford Chemicals (Canada) as a 35-40% alpha+beta punicalagin (by HPLC) pomegranate husk standard extract.

Punicalagin and other pomegranate components such as ellagic acid are also available as components of pomegranate extract or punica granatum extract (CAS No. 84961-57-9), a reddish- brown liquid, derived from pomegranate fruit extract and also as pomegranate juice, pomegranate seed oil, pomegranate husk or bark extract and pomegranate flower extract.

In some other embodiments, the FDC composition of this invention comprises at least one cannabinoid and punicalagin or punicalagin-containing plant extract, wherein the cannabinoid is used as in the form of cannabis essential oil or extract obtained from a plant selected from the group consisting of cannabis sativa, cannabis indica, and cannabis ruderalis.

In some other embodiments, the FDC composition of this invention comprises at least one cannabinoid and punicalagin. The punicalagin is used in the form of punicalagin plant isolate or punicalagin-containing plant extract or essential oil obtained from a plant selected from one or more species of the genus Lythraceae. Said Lythraceae species are selected from Punica granatum, P. protopunica and all the P. granatum cultivars. In addition, punicalagin may be obtained from one or more species of genus Myrtales, said Myrtales species being selected from Terminalia catappa, Terminalia myriocarpa and Combretum mode.

In some embodiments, the preferred species is Punica granatum.

In some embodiments, punicalagin is the compound of formula I in form alpha, beta or mixtures thereof.

Formula I Punicalagin is an ellagi tannin phenolic compound having molecular formula C48H28O30.

In some embodiments, the compositions of this inventions comprise punicalagin or its isomers, derivatives, salts, metabolites and mixtures thereof, in the form of essentially pure plant isolate or synthetic or as a component of a punicalagin-containing essential oil or extract. In some other embodiments, the at least one cannabinoid used in the FDC compositions of this invention is selected from the group consisting of tetrahydrocannabinol (THC), iso- tetrahydrocannabinol-type (iso-THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannahinol (CBN), cannabinolic acid (CBNA), cannabinol methyl ether (CBNM), cannabinol-C4 (CBN-C4), cannabinol-CZ (CBN-C2), cannabiorcol (CBN-C1), cannabinodiol (CBND), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerolic acid monomethyl ether (CBGAM), cannabigerol monomethyl ether (CBGM), cannabigerovarinic acid (CBGVA), cannabichromene (CBC), cannabichromanon (CBCN), cannabichromenic acid (CBCA), cannabichromevarin (CBCV), cannabichromevarinic acid (CBCVA), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabielsoin (CBE), cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), cannabigerovarin (CBGV), cannabidiolic acid (CBDA), cannabidiol monomethyl ether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic acid (CBDVA), and cannabidiorcol (CBD-C1), cannabicyclol (CBL), cannabicyclolic acid (CBLA), cannabicyclovarin (CBLV), cannabitriol, cannabitriolvarin (CBTV), ethoxy-cannabitiolvarin (CBTVE), cannabivarin (CBV), cannabidivarin (CBVD), cannabitriol, cannabitriolvarin (CBTV), ethoxy-cannabitiolvarin (CBTVE), cannabifuran (CBF), dehydrocannabifuran (DCBF), and cannabiripsol (CBR), pharmaceutically acceptable salts thereof, solvates, metabolites, metabolic precursors, isomers or derivatives thereof.

In some embodiments, the at least one cannabinoid used in the compositions of this invention is CBD.

In some other embodiments, the at least one cannabinoid used in the compositions of this invention is THC.

According to some embodiments, the composition of this invention is formulated in the form of a pharmaceutical composition, a nutraceutical, a cosmeceutical, a nutricosmetic, a cosmetic composition, a body care product, a personal hygiene product or a food product.

According to some embodiments, the composition of this invention is formulated as a single unit dosage form essentially comprising punicalagin or punicalagin-containing plant extract and at least one cannabinoid.

According to some other embodiments, the composition of this invention is formulated as two or more units of dosage forms, at least one of which comprises essentially pure punicalagin or punicalagin-containing plant extract, an punicalagin or punicalagin-containing plant extract- containing extract or a punicalagin or punicalagin-containing plant extract-containing essential oil, and at least one dosage form comprises cannabis plant extract, cannabis plant essential oil, or at least one essentially pure cannabinoid (e.g. CBD).

In some embodiments, the composition of this invention is a pharmaceutical composition selected from an anti-allergic agent, an anti-inflammatory agent, an immunomodulator, an antioxidant, an anti-microbial agent, an antibacterial agent, an antifungal agent, an antiviral agent, an antinociceptive agent, an analgesic agent, an anesthetic agent, an anti-cancer agent, an apoptosis inducing agent, an antiscorbutic agent, an antipyretic agent, an anti-malarial agent, an addiction mitigatory agent, an anxiolytic agent, an anti-depressant agent, a diuretic agent, an anti-diarrheal agent, a vasodilator and an aphrodisiac agent.

According to some embodiments, the composition of this invention is a pharmaceutical composition selected for use as anti-allergic, anti-inflammatory, immunomodulator, antioxidant, anti-microbial, antibacterial, antifungal, antiviral, antinociceptive, analgesic, anesthetic, anti-cancer, apoptosis inducing, antiscorbutic, antipyretic, anti-malarial, addiction mitigatory, anxiolytic, anti depressant, diuretic, anti-diarrheal, vasodilator or aphrodisiac.

In some embodiments, the composition of this invention is an anti-cancer agent.

In some other embodiments, the composition of this invention is a cosmeceutical or nu tricosmetic, for alleviating, treatment, curing, mitigating or preventing a dermatological disease or condition selected from acne, emption, bums, and cuts.

According to some embodiments, the composition of this invention is formulated as a body lotion, soap, body wash, moisturizer, self-tanner, hand cream, body scmb, sunscreen, bath product, toothpaste, soap, shampoo, mouth wash, deodorant, antiperspirant, or shaving soap.

According to some embodiments, the composition of this invention is a cosmetic composition selected from an anti-wrinkle composition, a moisturizing cream, a face mask, a makeup, and a lipstick.

According to some other embodiments, the composition of this invention is a body care product or a personal hygiene product, selected from a body lotion, a soap, a body wash, a moisturizer, a self-tanner, a hand cream, a body scrub, a sunscreen, a bath product, a toothpaste, a shampoo, a mouth wash, a dental floss, a deodorant, an antiperspirant, and a shaving product.

According to some embodiments, the composition of this invention may further comprise at least one additional ingredient selected from a phytochemical, an essential oil, a carrier oil, a antibacterial agent, an antioxidant (e.g., ascorbic acid or sodium bisulfite), an anti-inflammatory agent, anti-viral agent, an antifungal agent, an anti-microbial agent, a chemotherapeutic agent, an immune -oncology (10) agent, an immunoapoptosis inducing agent, an anti-diarrheal agent, an anti histamine, a probiotic, a vitamin, a colorant, a buffer, an emulsifier, a sun screen, a moisturizer, an analgesic agent, an anti-depressant agent, a skin nutrient, a medicinal herbal extract, a flavor, a flower essence, a protein, a lubricant, a buffering agent, a bulking agent (e.g. mannitol), a physiologically suitable carrier, and an inactive excipient.

In some embodiments, there is provided a method for treating, curing, mitigating or alleviating a disease, disorder or medical condition, comprising co-administering to a subject in need thereof a therapeutically effective amount of punicalagin or punicalagin-containing plant extract, whether as essentially pure drug or isolate or as plant extract or essential oil and a therapeutically effective amount of at least one of an essentially pure cannabinoid (e.g. CBD), a cannabis plant extract, or a plant essential oil, thereby treating, curing, mitigating or alleviating the disease, disorder or medical condition.

In some embodiments, there is provided a method for treating, curing, mitigating or alleviating a disease, disorder or medical condition, comprising co-administering to a subject in need thereof a therapeutically effective amount of punicalagin or punicalagin-containing plant extract, whether as essentially pure drug or isolate or as plant extract or essential oil and a therapeutically effective amount of at least one of an essentially pure cannabinoid (e.g. CBD), a cannabis plant extract, or a plant essential oil, administered together concomitantly.

In some embodiments, there is provided a method for treating, curing, mitigating or alleviating a disease, disorder or medical condition, comprising co-administering to a subject in need thereof a therapeutically effective amount of punicalagin or punicalagin-containing plant extract, whether as essentially pure drug or isolate or as plant extract or essential oil and a therapeutically effective amount of at least one of an essentially pure cannabinoid, a cannabis plant extract, or a plant essential oil, administered together consecutively..

According to some embodiments, there is provided a method of treatment of a disease, disorder or medical condition comprising administration of a therapeutically effective amount of a composition of this invention to a subject in need thereof, wherein the disease, disorder or medical condition is selected from a gastroenterologic disease, inflammation, an autoimmune disease, an immunodeficiency disease, a neurodegenerative disease, an oncologic disease, a cardiovascular disease, a mental or psychiatric disease, a skin disease, viral, bacterial or fungal infection, and blood vessels diseases or disorders. In some embodiments, there is provided a method of treatment of this invention, wherein the disease, disorder or medical condition is selected from nausea, appetite loss and pain associated with cancer and chemotherapy; nausea, appetite loss, pain and wasting associated with AIDS; toothache; cancer; arthritis and rheumatism; glaucoma; migraine; scurvy; muscle spasticity; alcohol and narcotics withdrawal; stress; asthma; Tourette syndrome, Cervical dystonia; epileptic seizures; dementia; dysmenorrhea; anxiety disorders; depression; diabetes; diarrhea; neuropathic pain; chronic pain; psoriasis; dermatitis; swimmer’s eczema; Alzheimer’s disease; Huntington disease; Parkinson; Lyme disease; post-traumatic stress disorder; malaria; vasoconstriction, allergy; edema; liver inflammation; schizophrenia; colitis; painful spasms; fibromyalgia; sexual disfunction; posttraumatic stress disorder (PTSD); sepsis; necrotizing soft tissue infections (NSTI); acute or chronic pancreatitis; opioid addiction; inflammatory bowel disease (IBD); non-alcoholic fatty liver disease (NAFLD); non-alcoholic fatty liver disease (NAFLD); and irritable bowel syndrome (IBS).

According to some embodiments, there is provided a method of treatment by administration of a therapeutically effective amount of a composition of the present invention of a patient in need thereof, wherein co-administration of punicalagin or punicalagin-containing plant extract and at least one cannabinoid results in a therapeutic effect selected from a synergistic effect, an additive effect, a potentiating effect and any combination thereof.

In some other aspects of the present invention, some embodiments thereof relate to herbal compositions, more particularly, but not exclusively, to compositions comprising cannabis and/or at least one cannabinoid, and punicalagin or punicalagin-containing plant extract.

In some embodiments, the at least one cannabinoid in the composition of this invention is cannabidiol (CBD).

The medicinal qualities of cannabis and punicalagin-producing plants as such, have been long known and appreciated. The present inventor envisaged that combining punicalagin and at least one cannabinoid in treating certain diseases, disorders or other physical and mental conditions traditionally treatable with punicalagin or punicalagin-containing plant extract and/or cannabinoids, will provide a potentiating effect and/or enhancing effect, for example, an additive therapeutic effect or a synergistic therapeutic effect. The synergistic effect was effectively proved to be strong (see Example 1).

The term“pure” as used herein for“pure punicalagin or punicalagin-containing plant extract” and“pure cannabinoid” is meant to describe the compound per se, a clean, stand-alone chemical entity. The term“extract” as used herein refers to a cmde plant extract which is a collection of cmde mixtures extracted from different parts of a plants, for example, flowers, roots, stem, leaves. The general procedures adopted for obtaining plant extract are collection of plant parts, drying, for example, air drying, powdering and extraction with water or solvents (polar, non-polar or both). The cmde extract is produced by evaporating the solvent. The extract is further purified or concentrated to obtain a“fine extract” used for isolation or separation of classes of compounds from the extract (alkaloids, tannins, phenolics, terpenoids etc.), or pure compounds by further processing the extract.

As used hereon, the terms’’plant essential oil”,“essential oil” and“oil” are interchangeable and refer to natural plant oil typically obtained by distillation, and having a chemical composition and organoleptic properties (e.g., fragrance) characteristic of the plant or other source from which it is extracted. The process of acquiring a plant's essential oil is a little more complex than extraction, as it must be obtained through distillation (hydro, steam or hydro-cum-steam). The liquid that is distilled off is the plant essence, and the very small amount of volatile liquid that is left behind is the essential oil. By further processing or distilling, essential oils may sometimes be obtained from extracts. To be noted,“essential oil” and“oil” as used herein constitutes the natural, volatile plant oil obtained by distillation of plant biomass, and essential oil obtained by refining a plant extract as defined herein, by subjecting it to further processes such as distillation.

There is a difference between plant essential oils and simple plant extracts. Often, it is the essential oils which carry the medicinal qualities. Embodied compositions described herein comprise either plant extracts or plant essential oils, or both.

Cannabinoids

Cannabis, also known as marijuana and by numerous other names, is known for use as a psychoactive dmg or medicine since ancient times. The medicinal use of oils and extracts derived from cannabis plant material has been growing in popularity. The main psychoactive component of cannabis is tetrahydrocannabinol (THC); it is one of 483 known compounds in the plant, including at least 144 other cannabinoids, such as cannabidiol (CBD), cannabinol (CBN) and tetrahydrocannabivarin (THCV).

Cannabis has been indicated for the reduction of nausea and vomiting during chemotherapy, improving appetite in people with HIV/AIDS, alleviation of chronic pain and muscle spasms. Research has also shown the ability of cannabinoids and other compounds found in cannabis to stimulate bone growth, aid sleep, inhibit bacterial cell growth, inhibit cancer cell growth, and alleviate or otherwise reduce the symptoms of cancer, epilepsy, autoimmune diseases, neurodegeneration, Alzheimer’s disease, Lyme disease, post-traumatic stress disorder, and inflammation. Furthermore, extracts of cannabis plant material, whether ingested or inhaled, have also been shown to have therapeutic effects in patients with glaucoma, dysmenorrhea, migraines, anxiety disorders, or a combination thereof.

As used herein the term“cannabis” refers mainly to the genus of flowering plants that includes the three species (also referred to herein as“strains”), Cannabis sativa, Cannabis indica and Cannabis ruderalis. Other strains of cannabis from which plant material can be extracted and used in accordance with embodiments of the invention, include, but are not limited to: AC/DC, Afghan Goo, Atomic Northern Lights, Blackberry Kush, Bluebeny, Blueberry Kush, Blueberry Muflin Top, Blueberry OG, Blue Diesel, Blue Dream, Buddha Passion, Cannatonic, Chocolate Kush, Fire OG, Jilly Bean, Gran Daddy, Grape Blackberry Kush, Harle OG, Harle Tsu, Harlequin, Hope Springs, Infinite Euphoria, Long Valley, Royal Kush, Medihaze, Pineapple Jack, Prize Kush, Sour, Diesel, Sour Kush, and Tahoe OG.

The terms“strain” and“species” as used herein are interchangeable and refer to different varieties of a particular plant genus. For example, the term strain (or species) can refer to different variants of a cannabis plant. Different cannabis strains often exhibit distinct chemical compositions with characteristic levels of cannabinoids and terpenes, as well as other components. Different cannabinoids and terpenes profiles associated with different cannabis strains can be useful in the treatment of different diseases, or for treating different subjects with the same disease. For example, the species Cannabis ruderalis is substantially devoid of cannabinoids which exert psychotropic activity.

The terms“cannabis oil” (or the interchangeable terms“cannabis plant oil” and“cannabis plant essential oil”) and“cannabis extract” (or the interchangeable term“cannabis plant extract”) as used herein, refer to a mixture of compounds obtained from the distillation and extraction of cannabis plants, respectively.

Cannabis essential oil is a concentrated, sticky, green liquid and is considered highly volatile.

Cannabis extract is obtainable from cannabis plant material which includes cannabis flowers, buds, trichomes, leaves, stems, portions therein or combinations thereof. In some embodiments, the cannabis plant material consists of cannabis buds. The buds can be whole buds or buds that are cut or broken into pieces.

Cannabis plant essential oil is a wildly beneficial essential oil, considered as one of the most effective oils for the alleviation of certain illnesses and conditions. Cannabis essential oil is extracted by steam distillation from the flowers and upper leaves of cannabis plants. Aside from its extensive medical applications, it is also found in perfumes, soaps, and candles, as well as some use in foods. Considering that this oil is so powerful, very small amounts are sufficient for it to have an effect.

Numerous methods are known in the art to extract oil from the cannabis plant and the ordinary skilled artisan will know which to choose according to the intended use. See, for example, U.S. Patent Publication No. 2016/0346339 which is hereby incorporated by reference in its entirety.

“Cannabinoid” as used herein is a chemical compound that shows direct or indirect activity at a cannabinoid receptor (CNR). There are two main cannabinoid receptors, CNR1 (also known as CB1) and CNR2 (also known as CB2). Other receptors that have been indicated as having cannabinoid activity include the GPR55, GPR18, and TRPV1 receptors.

Cannabinoids, as referred to herein, include chemically synthesized cannabinoids and “phytocannabinoids”, namely cannabinoids that occur in a plant species or are derived from cannabinoids produced, e.g., by a cannabis plant species. Cannabinoids as used herein further include pharmaceutically acceptable salts, solvates, metabolites, metabolic precursors, isomers or derivatives of cannabinoids.

An example of a cannabinoid derivative is an acidic cannabinoid, namely a natural cannabinoid having one or more carboxylic acid functional groups. Examples of acidic cannabinoids include, but are not limited to, tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), and cannabichromenic acid (CBCA). Acidic cannabinoids are frequently the predominant cannabinoids found in raw cannabis plant material.

Further cannabinoids and compounds derived therefrom or related thereto are disclosed, for example, in U.S. Patent Publication No. 2016/0346339, hereby incorporated by reference in its entirety.

As used herein, the term“at least one cannabinoid” is meant to refer to one cannabinoid or a combination of at least two cannabinoids, for example, any combination of two, three, four, five, six, ten or even more of any of the cannabinoids defined or described herein, whether naturally occurring cannabinoids (phytocannabinoids), chemically synthetized cannabinoid, or pharmaceutically acceptable salts thereof, solvates, metabolites, metabolic precursors, isomers or derivatives thereof.

In some embodiments, the composition described herein comprises THC and/or CBD.

As used herein the term“cannabidiol” or“CBD” refers to the major non-psychotropic cannabinoid in most cannabis preparations, such as hashish and marihuana. Thus, cannabidiol, as used herein, is meant to refer to 2-[3-methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl]-5-pentyl-l,3- benzenediol, whether the naturally occurring substance or synthetic versions of same, as well as to pharmaceutically acceptable salts, solvates, metabolites (e.g., cutaneous metabolites), and metabolic precursors of CBD. Some cannabidiol derivatives and metabolites thereof are taught, for example, in U.S. Patents Nos. 7,759,526, 8,119,697 and 8,435,556, each of which is hereby incorporated by reference in its entirety. The synthesis of CBD is described, for example, in Petilka et al., Helv. Chim. Acta, 52:1102 (1969) and in Mechoulam et al., J. Am. Chem. Soc., 87:3273 (1965), which are hereby incorporated by reference.

As used herein the term“tetrahydrocannabinol” or“THC”, or more precisely its main isomer (-)-trans-A⁹-tetrahydrocannabinol ((6aR,l0aR)-delta-9-tetrahydro- cannabinol), is the principal psychoactive cannabinoid of some strains of cannabis. The term refers to the naturally occurring substance or synthetic versions of same. Herein, THC, also refers to pharmaceutically acceptable salts, solvates, metabolites, and metabolic precursors of (-)-trans-A⁹- tetrahydrocannabinol. A⁹-tetrahydrocannabinol is marketed under the generic name "dronabinol".

The cannabinoids, for example, THC and/or CBD can be provided to the composition described herein in a purified form (e.g., above 90% purity, e.g., synthetic forms) or in a cannabis essential oil (e.g., obtained from trichome extract). The oil can be extracted from a single strain of a cannabis or from a plurality of strains (or genetic backgrounds), wherein the cannabis genetic background is selected according to the intended use, for example, high/low CBD/THC levels.

Breeders are currently developing more CBD-rich strains, as reported in Good, Alastair (26 October 2010), "Growing marijuana that won’t get you high", The Daily Telegraph (London). Other CBD-rich strains are available from Tikun Olam that developed a strain of the plant which has only cannabidiol as an active ingredient, and no detectable levels of THC, providing some of the medicinal benefits of cannabis without the psychotropic effects. Avidekel, a cannabis strain that contains 15.8% CBD and less than 1% THC can also be used according to the present teachings. Alternatively, strains of cannabis containing higher levels of THC than levels of (or no) CBD may be desirable for treating certain medical conditions, such as, for example, conditions causing chronic pain.

In some embodiments, any variety of cannabis strains and/or hemp may be used provided that there is a minimum of 1% CBD and/or THC.

CBD and/or THC can be extracted using any of the methods taught in the art. Extraction methods include, but are not limited to, CCT extraction, butane extraction, alcohol (e.g., ethanol) extraction, and oil extraction. In the latter, various oils can be used, including, but not limited to, vegetable oils (e.g., olive oil, avocado oil), nut oils (e.g., almond oil, pecan oil, walnut oil), canola, coconut oil, sesame oil, grape seed oil, hemp seed oil, butter and the like.

When cannabis essential oil or cannabis extract is used as the source of CBD/THC or any other cannabinoid, the composition described herein comprises also other phytochemicals and active ingredients which are distilled/extracted in the cannabis oil/extract. Examples include, but are not limited to, other cannabinoids, terpenes (monoterpenes, sesquiterpenes), terpenoids, and other compounds found in the cannabis plant. The exact composition of cannabis oil or cannabis extract will depend on the strain of cannabis that is used for distillation/extraction, the process of the distillation/extraction utilized and its efficiency. Such compounds are easily identified using gas chromatography or HPLC (see for details Romano et al. Cannabinoids l(l):l-l l, 2013). Cannabis oil or cannabis extract may further comprise additives that may have been incorporated to alter the palatability or improve administration of the cannabis oil or extract.

Punicalagin

The punicalagin or punicalagin-containing plant extract may be purified as described herein infra. Alternatively, or additionally, compositions as described herein may comprise chemically synthesized punicalagin or punicalagin-containing plant extract.

The amount of punicalagin or punicalagin-containing plant extract that can be extracted, e.g., from plant roots, leaves or flowers, depends, to some extent, on the extraction method used. Thus, extractions with, e.g., different solvents/eluents, may provide different yields of extractable punicalagin or punicalagin-containing plant extract. Typically, 10-20% of material may be extracted from pomegranate fruit, dry leaves, stems, bark or flowers, preferably from the bark.

Non-limiting examples of punicalagin or punicalagin-containing plant extract extraction processes include use of supercritical CCT with added ethanol and water to extract punicalagin or punicalagin-containing plant extract. After being extracted, punicalagin or punicalagin-containing plant extract can be separated from the other components in the extract, and subsequently purified using any of the methods and techniques known in art, for example, by molecular distillation, thin-hlm distillation, or a chromatography method such as preparative scale thin layer chromatography (TLC) and/or high- pressure liquid chromatography (HPLC), and such purihcation methods may be used alone or in appropriate combinations to obtain high yield of pure punicalagin or punicalagin-containing plant extract.

For quantitation, both HPLC with UV detection and liquid chromatography-mass spectroscopy (LC-MS) may be employed.

In some embodiments, the composition described herein comprise punicalagin or punicalagin-containing plant extract or essential oil.

The terms“punicalagin or punicalagin-containing plant extract” and“punicalagin-containing containing essential oil” as used herein, refer to a mixture of compounds obtained from the extraction/distillation of punicalagin-containing plants, dissolved or suspended in the extraction/oil as described herein, using any of the applicable extraction methods or distillation and/or other means used to produce volatile essential oils from plants, respectively, as taught in the art.

Extracts and essential oils containing punicalagin may be obtained from the whole plant or form a part thereof, e.g., flowers, leaves, stem, bark or roots.

The extract/oil obtained from punicalagin-containing plant contains a diverse group of compounds.

The exact composition of punicalagin-containing plant extract or essential oil will depend on the punicalagin-containing plant that is being extracted, the efficiency of the extraction/distillation process, and any additives that might be incorporated to alter the palatability or improve administration of the extraction/oil.

Punicalagin or punicalagin-containing plant extract or essential oils may be used without purihcation so long as their tastes and odors do not adversely affect the flavor and/or odor of the compositions comprising same. From the viewpoint of safety, it is preferred to use extracts or essential oils obtained from proven edible plants.

Medicinal uses of punicalagin

In traditional medicine, punicalagin or punicalagin-containing plant extract is well known, inter alia, for its anti-oxidative, analgesic and anti-inflammatory effects. Punicalagin-containing plant extract or punicalagin-containing essential oil comprising the amount and form of punicalagin naturally extractable from a particular species of plant that produces punicalagin are herein referred to as a“natural extract” or a“natural oil”, respectively.

Compositions

Cannabis oil or cannabis extract used in accordance with embodiments of the invention can contain any number and type of cannabinoids and other extractable metabolites and compounds (e.g., terpenes, terpenoids) as described herein.

Besides the natural extracts and oils of cannabis, compositions described herein may be fortified or enriched with additional cannabinoids, which may be the same cannabinoids as those present in the natural extract/oil, or alternatively or additionally, cannabinoids differing from the cannabinoids naturally present in a given extract or oil.

The additional, same or different, cannabinoids may be provided to the composition either in their purified form, or, alternatively, they can be components of one or more cannabis extracts or oils which are admixed with the natural extract or oil. The one or more additional extracts or oils may be natural extracts or oils obtained from the same strain of cannabis but using, e.g., different extraction methods or conditions, or different parts of the plant, or same strain grown under different conditions or geographic zones. Alternatively, or additionally, the one or more additional extracts may be obtained from different strains of cannabis. The terms“cannabis extract” and “cannabis oil” encompass all variation of natural and enriched extracts and oils, respectively, as defined hereinabove.

The amounts of any cannabinoid for example, CBD and/or THC, as well as the amounts of punicalagin or punicalagin-containing plant extract in the composition may vary according to the intended use of the composition.

The compositions described herein facilitate co -administration of cannabinoids and punicalagin or punicalagin-containing plant extract for use in any need that may benefit from synergistic, additive or potentiating therapeutic or non-therapeutic (e.g., cosmetic, personal hygiene) effect exerted by co-application of punicalagin or punicalagin-containing plant extract and cannabinoids, such as, but not limited to, the diseases and conditions that are affected or are treatable by punicalagin or punicalagin-containing plant extract consumption when applied alone or by cannabinoids consumption as described herein when applied alone.

Punicalagin or punicalagin-containing plant extract and cannabinoids may be combined together and be provided as a stand-alone crude admixed composition. Alternatively, punicalagin or punicalagin-containing plant extract and cannabinoids can be formulated e.g., as pharmaceutical compositions, cosmeceutical, cosmetic compositions, body care compositions, personal hygiene composition or food products, were they are mixed with suitable carriers, excipients and, optionally, further active agents.

The composition as described herein may be formulated as a single unit dose form essentially comprising a mixture of punicalagin or punicalagin-containing plant extract and at least one cannabinoid either in their purified form and/or provided in extracts or essential oils as described herein.

Alternatively, or additionally, the composition described herein may be provided in two or more units of dosage form, at least one of which comprises punicalagin or punicalagin-containing plant extract, or punicalagin-containing essential oils, and at least one dosage form comprising a cannabinoid, cannabis plant extract or cannabis plant essential oil.

When formulated as separate dosage forms, punicalagin or punicalagin-containing plant extract or punicalagin-containing plant material and cannabis or at least one cannabinoid may be administered via the same route of administration, for example orally by eating or drinking. Additional, or alternatively, two or more different routes of administration may apply. For example, cannabis plant material may be administered via inhalation and/or consumption of marijuana- infused food and drink, and punicalagin or punicalagin-containing plant extract may be administrated by chewing punicalagin or punicalagin-containing plant extract or plant material.

The compositions described herein may be formulated and provided as pharmaceuticals composition or medicaments for curing, treating, mitigating or preventing a number of diseases and conditions including, but not limited to, cancer, headaches, inflammation, allergy, bacterial or viral infections, vertigo, body aches, and glaucoma. Thus, the pharmaceutical composition described herein is selected from an anti-allergic medication, an anti-inflammatory medication, an antioxidant, an anti-microbial medication, an antibacterial medication, an antifungal medication, an antiviral medication, an analgesic medication, an anti-cancer medication, an apoptosis inducing medication and an anti-diarrheal medication.

In some embodiments, the pharmaceutical is an anti-cancer agent or medication.

The compositions described herein may also be formulated and provided as cosmeceuticals or as nutricosmetic compositions for combining beauty care with treating, mitigating, curing or preventing dermatological diseases and conditions such as, but not limited to, acne, eruption, burns, and cuts. As used herein, the term “cosmeceutical” refers to a cosmetic product with bioactive ingredients purported to have medical or dmg-like benefits. The "cosmeceutical" label applies only to products applied topically, such as creams, lotions and ointments. Products which are similar in perceived benefits but ingested orally are termed herein“nu tricosmetics”.

For example, the composition described herein may be used in the manufacture of anti-acne cream or paste.

The compositions described herein may be formulated and provided as cosmetics or “cosmetic formulations”, namely vehicles in the form of emulsions, lotions, creams, gels, ointments, foams and the like, that comprise punicalagin and at least one cannabinoid as described herein, together with known cosmetic ingredients applied in skincare formulations or makeup products, for example, colorants, buffers, emulsifiers, sun screeners, moisturizers, skin nutrients and the like.

Cosmetics and cosmeceuticals, also sometimes collectively referred to herein as“beauty products”, are formulated in a form suitable, e.g., for topical application on an applied area, and may be used as anti-wrinkles, moisturizing creams, face masks, makeup, lipsticks and the like. A beauty product in accordance with some embodiments, may be in the form of a cream, an ointment, a paste, a gel, a lotion, a milk, an oil, a suspension, a solution, an aerosol, a spray, a foam, or a mousse.

For example, the composition described herein may be utilized in the manufacture of anti wrinkle cream that can substitute for Botox in cosmetic applications, or be added to anti-aging products. In another example, the composition described herein may be formulated and use as a skin penetration enhancer.

Composition as described herein may be formulated as body care products such as body lotions, soaps, body washes, moisturizers, self-tanners, hand cream, body scmb, sunscreen, bath products, or hygiene products such as toothpaste, soaps, shampoos, mouth wash, dental floss, deodorants, antiperspirants, shaving product such as shaving soap, gel or foam, and the like.

For example, the composition described herein may be used in the manufacture of toothpaste or be used as oral analgesic gel or paste.

The compositions described herein may also be added to food products, for example, to spices and be consumed by eating or drinking.

When formulated as pharmaceutical compositions or medicaments, cosmeceuticals or cosmetics, the compositions can be formulated by standard techniques or methods well-known in the art of pharmacy and cosmetics using one or more physiologically acceptable carriers or excipients. Suitable pharmaceutical carriers are described herein and in, e.g., “Remington’s Pharmaceutical Sciences” by E. W. Martin.

As used herein a "pharmaceutical composition" refers to a preparation comprising punicalagin or punicalagin-containing plant extract and at least one cannabinoid as described herein (as active ingredient), or physiologically acceptable salts or prodmgs thereof, with other chemical components including but not limited to physiologically suitable carriers, excipients, lubricants, buffering agents, antibacterial agents, bulking agents (e.g. mannitol), antioxidants (e.g., ascorbic acid or sodium bisulfite), anti-inflammatory agents, anti-viral agents, chemotherapeutic agents, anti histamines and the like, as further described infra. The purpose of a pharmaceutical composition is to facilitate administration of the active agents to a subject. The term "active ingredient" refers to a compound, which is accountable for a desired biological effect.

As used herein, the term "physiologically acceptable" or“pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

Herein, the phrase "pharmaceutically acceptable carrier" refers to an approved carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of a possible active agent.

Herein the term "excipient" refers to an inert substance added to a pharmaceutical or to a cosmetic composition to further facilitate processes and administration of the active ingredients. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

Techniques for formulation and administration of drugs may be found in“Remington’s Pharmaceutical Sciences” Mack Publishing Co., Easton, PA, latest edition, which is incorporated herein by reference.

Pharmaceutical compositions, cosmeceutical and cosmetic compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers or cosmetically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the compounds into preparations which can be used pharmaceutically or cosmetically. Proper formulation is dependent upon the route of administration chosen. For pharmaceutical compositions, the dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see e.g., Fingl et ah, 1975, in“The Pharmacological Basis of Therapeutics”, Ch. 1 p.l).

Since the present teachings relate to the production of compositions which are endowed with pharmaceutical activities and/or cosmetic activities, the composition may further comprise other active agents such as pharmaceutical agents, plant extracts with medical and/or cosmetic use, essential oils, semms, proteins, vitamins and the like.

In some embodiments, the pharmaceutical agent is a phytochemical, namely, a chemical compound produced by plants through primary or secondary metabolism. Phytochemicals generally have biological activity in the plant host and play a role in plant growth or defense against competitors, pathogens, or predators. Examples of such phytochemicals include, but are not limited to, terpenoids, flavonoids, tannins, phenols, saponins, polyphenols, heterosides, alkamides and alkaloids.

Examples of medicinal plants from which active ingredients may be extracted and provided to the compositions described herein include, but are not limited to, Salvia sclarea, Echinacea purpurea, extracts from citruses. Examples of active ingredients include, but are not limited to, heterosides: anthraquinones, cardiac glycosides, cyanogenics; coumarins flavonoids, phenols, ranunculosides, saponosides, sulphurides; polyphenols: phenolic acids, coumarins, flavonoids, lignans, tannins, quinine; and terpenoids: essential oils, iridoids, lactones, diterpenes, saponins.

In some embodiments, the pharmaceutical agent is not naturally present in (i.e., endogenous to) the cannabis trichome or cannabis oil nor to the punicalagin-containing plant extract.

In some embodiments, the pharmaceutical agent is an antibacterial agent, an antioxidant (e.g., ascorbic acid or sodium bisulfite), an anti-inflammatory agent, an anti-viral agent, an antifungal agent, an anti-microbial agent, a chemotherapeutic agent, an apoptosis inducing agent, an anti-diarrheal agent, an anti-histamine, an analgesic agent, and/or an anti-depressant agent.

The composition may comprise from about 0.1% to about 10% by weight or by volume of a pharmaceutical or otherwise active agent, for example, 0.1-1.0%, 0.1-0.9%, 0.1-0.8%, 0.1-0.7%, 0.1-0.6%, 0.1-0.5%, 0.1-0.3%, 0.l-0.2%, 1-5%, 2-5%, 2-6%, 3-8%, 4.0-9%, 5-8%, 6-9 %,5-l0%, 7- 10%, or 9-10%, by weight or by volume. For example, a composition in accordance with the invention may be formulated as a psoriasis cream that contains CBD, punicalagin and about 3% salicylic acid as the pharmaceutical agent.

The compositions described herein may comprise one or more essential oils which are not necessarily originating from a cannabis plant or a punicalagin or punicalagin-containing plant. Such essential oils are added to the compositions to provide properties such as improved palatability. Essential oils can also provide antioxidant and preservative properties to the compositions. The identity and amount of the essential oil(s) added can depend in part on factors including the strain of cannabis and/or the punicalagin or punicalagin-containing plant extract-producing plant that has been extracted, and the desired organoleptic properties.

In general, the amount of total essential oils added to a composition will range from about 0.01% (w/w) to about 10% (w/w) or more. The total amount of essential oils added can range, for example, from about 0.01% (w/w) to about 0.5% (w/w), or from about 0.5% (w/w) to about 1% (w/w), or from about 1% (w/w) to about 2% (w/w), or from about 2% (w/w) to about 3% (w/w), or from about 3% (w/w) to about 4% (w/w), or from about 4% (w/w) to about 5% (w/w), or from about 5% (w/w) to about 6% (w/w), or from about 6% (w/w) to about 7% (w/w), or from about 7% (w/w) to about 8% (w/w), or from about 8% (w/w) to about 9% (w/w), or from about 9% (w/w) to about 10% (w/w).

For example, the amount of total essential oils added may about 0.05%, about 1%, or about 2% (w/w). The % (w/w) values indicated are based on the amount of essential oil added to the total amounts of other ingredients and constituents of the composition. Examples of essential oils include, but are not limited to, bergamot essential oil, blood orange essential oil, sweet orange essential oil, neroli essential oil, peppermint essential oil, lavender essential oil, lemongrass essential oil, vanilla essential oil and spearmint essential oil. Other essential oils that can be added to the compositions described herein are disclosed in U.S. Patent Publication No. 2016/0346339 hereby incorporated by reference in its entirety.

In some embodiments, additional carrier oils are added to the compositions as described herein. Examples of carrier oils include, but are not limited to: almond oil; aloe vera oil; apricot kernel oil; avocado oil; argan oil; calendula oil; carrot seed oil; castor oil; coconut oil; evening primrose oil; bsh oils and oils rich in omega-3 fatty acids (e.g., algae, krill, flaxseed); grape seed oil; hazelnut oil; hemp seed oil; jojoba oil; macadamia oil; olive oil; raspberry seed oil; sesame oil; sunflower oil; walnut oil; wheatgerm oil; and combinations thereof. In some embodiments, the carrier oil is hemp seed oil.

When added, a carrier oil will typically be present in an amount ranging from about 1 % (w/w) to about 95% (w/w).

The composition described herein may comprise vitamins, such as, but not limited to, vitamin A, vitamin B, vitamin C, vitamin D, vitamin E and vitamin K.

It will be appreciated that other ingredients may be added to the composition. Such ingredients may include, but are not limited to, probiotics, coloring agents, emulsifiers, herbal extracts with medical uses, flavors, flower essences and proteins.

The amount of the at least one cannabinoid either purified or synthetic or cannabis extract or cannabis oil in the composition may vary from 0.1 % to 99.9% in accordance with the intended use of the composition. Likewise, the amount of punicalagin or punicalagin-containing plant extract or punicalagin-containing essential oil or purified isolate or synthetic punicalagin in the composition may vary from 0.1% to 99.9% in accordance with the intended use of the composition.

In some embodiments, the cannabis extract or cannabis oil or any specific cannabinoid is present in the composition in an amount of at least 10%, at least 20%, at least 50%, at least 60%, at least 65%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, or at least 99.8%.

In some embodiments, the composition comprises 50-99.9%, 60-99.9%, 70-99.9%, 80-99%, 90-99.9%, 95-99.9%, 96-99.9%, 97-99.9%, 98-99.9%, 50-90%, 60-90%, 70-90%, 80-90%, 60-80%, 60-70%, 65-75%, 60-95%, 70-95%, 80-95%, 90-95%, 95-99%, 97-99%, or 98-99% of cannabis extract and/or cannabis oil and/or any specific cannabinoid, either purified plant isolate or synthetic.

In some embodiments, the composition comprises 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5- 25%, 5-20%, 5-15%, 5-12%, 5-10%, 5-8%, 5-7%, 5-6%, 10-45%, 10-40%, 10-35%, 15-30%, 15- 25%, 15-20%, 20-50%, 20-40%, 25-40%, 30-45%, 35-40%, or 40-50% of cannabis extract and/or cannabis oil and/or at least one cannabinoid, either as purified plant isolate or synthetic.

In some embodiments, the cannabis oil or cannabis extract or at least one cannabinoid may be present in the composition at an amount not exceeding 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.5%, 0.4%, 0.3% or 0.2%.

In some embodiments, the composition comprises 0.1-5%, 0.1-4.5%, 0.1-4.0%, 0.1-3.5%, 0.1-3.0%, 0.1-2.5%, 0.1-2.0%, 0.l-l.5%, 0.l-l.2%, 0.l-l .0%, 0.l-0.8%, 0.l-0.5%, 0.l-0.4%, 0.1- 0.3%, or 0.1 -0.2% of cannabis extract and/or cannabis oil and/or at least one cannabinoid, either purified isolate or synthetic.

In some embodiments, the essentially pure punicalagin or punicalagin -containing plant extract or punicalagin-containing essential oil is present in the composition in an amount of at least 30%, at least 35%, at least 40%, 50%, at least 60%, at least 65%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, or at least 99.8% in w/w percent.

In specific embodiments, the composition comprises 30-50%, 50-99.9%, 60-99.9%, 70- 99.9%, 80-99%, 90-99.9%, 95-99.9%, 96-99.9%, 97-99.9%, 98-99.9%, 50-90%, 60-90%, 70-90%, 80-90%, 60-80%, 60-70%, 65-75%, 60-95%, 70-95%, 80-95%, 90-95%, 95-99%, 97-99%, or 98- 99% in w/w percent of punicalagin or punicalagin-containing plant extract or punicalagin- containing essential oil.

In some embodiments, the essentially pure punicalagin or punicalagin-containing plant extract or punicalagin-containing essential oil is present in the composition at an amount not exceeding 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.5%, 0.4%, 0.3% or 0.2%.

In some embodiments, the composition comprises 0.1-5%, 0.1-4.5%, 0.1-4.0%, 0.1-3.5%, 0.1-3.0%, 0.1-2.5%, 0.1-2.0%, 0.l-l.5%, 0.l-l.2%, 0.l-l .0%, 0.l-0.8%, 0.l-0.5%, 0.l-0.4%, 0.1- 0.3%, or 0.1 -0.2% of essentially pure punicalagin or punicalagin-containing plant extract or punicalagin-containing essential oil.

In some embodiments, the composition comprises 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5- 25%, 5-20%, 5-15%, 5-12%, 5-10%, 5-8%, 5-7%, 5-6%, 10-45%, 10-40%, 10-35%, 15-30%, 15- 25%, 15-20%, 20-50%, 20-40%, 25-40%, 30-45%, 35-40%, or 40-50% of essentially pure punicalagin or punicalagin-containing plant extract or punicalagin-containing essential oil.

In exemplary embodiments, the composition comprises 10-600 mg/gr, 10-200 mg/gr, 10-100 mg/gr, 50-100 mg/gr CBD and/or THC.

In exemplary embodiments, the composition comprises 10-600 mg/g, 10-200 mg/gr, 10-100 mg/gr, 50-100 mg/gr punicalagin or punicalagin-containing plant extract.

Of note, water can be added to the composition in order to dilute the active ingredients. According to specific embodiments, the water present does not exceed 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15% or 10%.

In an exemplary embodiment, the composition comprises: 50-99.9 % at least one essentially pure cannabinoid, cannabis oil or cannabis extract;

1-45 % essentially pure punicalagin or punicalagin-containing plant extract or oil; and optionally

0.1-5 % an active pharmaceutical ingredient (API).

In accordance with this particular embodiment, the composition is prepared by mixing the essentially pure at least one cannabinoid, cannabis oil or cannabis extract with essentially pure punicalagin or punicalagin-containing plant extract or essential oil, both of which are optionally mixed with a pharmaceutically acceptable carrier, and optionally with the API. Other ingredients such as described herein can be added.

In an exemplary embodiment, cannabis oil and/or cannabis hemp flowers in the form of a cake or powder are added to liquid mixture containing punicalagin or punicalagin-containing plant extract or essential oil. The composition is mixed by shaking. Finally, other ingredients such as natural coloring agents are added. The components are mixed until reaching a homogeneous composition. Typically, mixing is done while heating (e.g., to 75 °C).

Of note, all percentages indicated herein refer to w/w.

The composition described herein can be formulated for administration by any suitable route, including, but not limited to, orally, topically, nasally, rectally, vaginally, pulmonary, parenterally (e.g., intravenously, subcutaneously, intramuscularly, etc.), and any combinations thereof. In some embodiments, the composition is diluted in a liquid, e.g., a carrier oil. The most suitable route of administration in any given case will depend in part on the condition being treated as well as the response of the subject to the particular route of treatment.

In some embodiments, compositions as described herein are administered via a vaporizer or like device as described, for example, in U.S. Patent No. 8,915,254; U.S. Patent Application Publication No. 2014/0060552; U.S. Patent No. 8,488,952; and U.S. Patent Application Publication No. 2015/0040926.

Compositions for pulmonary administration also include, but are not limited to, dry powder compositions consisting of the powder of at least one essentially pure cannabinoid, a cannabis extract, essentially pure punicalagin or punicalagin-containing plant extract or punicalagin or punicalagin-containing plant extract or oil described herein, and the powder of a suitable carrier and/or lubricant. The compositions for pulmonary administration can be inhaled from any suitable dry powder inhaler device known to a person skilled in the art. In certain instances, the compositions may be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluorome thane, trichlorofluoromethane, dichlorotetrafluoroe thane, carbon dioxide, or other suitable gas.

In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the ingredients of the composition and a suitable powder base, for example, lactose or starch.

For oral administration, a pharmaceutical composition or a medicament can take the form of, e.g., a tablet or a capsule prepared by conventional means with a pharmaceutically acceptable excipient. Preferred are tablets and gelatin capsules comprising the active ingredient(s), together with (a) diluents or hllers, e.g., lactose, dextrose, sucrose, mannitol, maltodextrin, lecithin, agarose, xanthan gum, guar gum, sorbitol, cellulose (e.g., ethyl cellulose, microcrystalline cellulose), glycine, pectin, polyacrylates and/or calcium hydrogen phosphate, calcium sulfate, (b) lubricants, e.g., silica, anhydrous colloidal silica, talcum, stearic acid, its magnesium or calcium salt (e.g., magnesium stearate or calcium stearate), metallic stearates, colloidal silicon dioxide, hydrogenated vegetable oil, corn starch, sodium benzoate, sodium acetate and/or polyethylene glycol (PEG); for tablets also (c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and/or hydroxypropyl methylcellulose; if desired (d) disintegrants, e.g., starches (e.g., potato starch or sodium starch), glycolate, agar, alginic acid or its sodium or potassium salt, or effervescent mixtures; (e) wetting agents, e.g., sodium lauryl sulfate, and/or (f) absorbents, colorants, flavors and sweeteners. Tablets can be either uncoated or coated according to methods known in the art.

The excipients described herein can also be used for preparation of buccal dosage forms and sublingual dosage forms (e.g., films and lozenges) as described, for example, in U.S. Patent Nos. 5,981,552 and 8,475,832. Formulation in chewing gums as described, for example, in U.S. Patent No. 8,722,022, is also contemplated.

Further preparations for oral administration can take the form of, for example, solutions, syrups, suspensions, and toothpastes. Fiquid preparations for oral administration can be prepared by conventional means with pharmaceutically acceptable additives, for example, suspending agents, for example, sorbitol syrup, cellulose derivatives, or hydrogenated edible fats; emulsifying agents, for example, lecithin, xanthan gum, or acacia; non-aqueous vehicles, for example, almond oil, sesame oil, hemp seed oil, fish oil, oily esters, ethyl alcohol, or fractionated vegetable oils; and preservatives, for example, methyl or propyl-p-hydroxybenzoates or sorbic acid. The preparations can also contain buffer salts, flavoring, coloring, and/or sweetening agents as appropriate.

Typical formulations for topical administration include creams, ointments, sprays, lotions, hydrocolloid dressings, and patches, as well as eye drops, ear drops, and deodorants. The compositions described herein can be administered via transdermal patches as described, for example, in U.S. Patent Application Publication No. 2015/0126595 and U.S. Patent No. 8,449,908.

Formulation for rectal or vaginal administration is also contemplated. The composition can be formulated, for example, as suppositories containing conventional suppository bases such as cocoa butter and other glycerides as described in U.S. Patent Nos. 5,508,037 and 4,933,363. Compositions can contain other solidifying agents such as shea butter, beeswax, kokum butter, mango butter, illipe butter, tamanu butter, carnauba wax, emulsifying wax, soy wax, castor wax, rice bran wax, and candelila wax. Compositions can further include clays (e.g., Bentonite, French green clays, Fuller’s earth, Rhassoul clay, white kaolin clay) and salts (e.g., sea salt, Himalayan pink salt, and magnesium salts such as Epsom salt).

The compositions set forth herein can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, optionally with an added preservative. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are preferably prepared from fatty emulsions or suspensions.

The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other ingredients.

Alternatively, the compositions can be in powder form for reconstitution with a suitable vehicle, for example, a carrier oil, before use. In addition, the compositions may also contain other therapeutic agents or substances.

The compositions can be prepared according to conventional mixing, granulating, and/or coating methods, and contain from about 0.1 to about 75%, preferably from about 1% to about 50%w/w, of the total active ingredients.

In general, subjects receiving a composition orally are administered amounts ranging from about 1 to about 2000 mg of at least one essentially pure cannabinoid, cannabis oil or cannabis extract, from about 1 to about 500 mg of essentially pure punicalagin or from about 10 to about 2000 mg of punicalagin-containing extract or oil. A small dose ranging from about 1 to about 20 mg of the whole composition can typically be administered orally when treatment is initiated, and the dose can be increased (e.g., doubled) over a period of days or weeks until the maximum dose is reached. Pharmaceutical compositions may be administered for example, during 28 days.

The pharmaceutical compositions, cosmeceu deals, cosmetic compositions, food products, body care products, personal hygiene products and the like described hereinabove are packaged in a packaging material and identified in print, in or on the packaging material, for use in the relevant application.

Methods of treatment

According to a further aspect of the invention, there is provided a method of treating, curing or alleviating a disease, disorder or medical condition which is treatable and/or alleviated by at least one cannabinoid, cannabis and by punicalagin or punicalagin-containing plant extract, the method comprising co-administering to a subject in need thereof effective amounts of punicalagin or punicalagin-containing plant extract and of at least one cannabinoid and/or cannabis extract, thereby treating, curing or alleviating the disease, disorder or medical condition.

In some embodiments, the effective amount is a therapeutically effective amount of punicalagin or punicalagin-containing plant extract and/or of at least one cannabinoid or of the cannabis extract, namely an amount which will cure, treat, mitigate or prevent disease or will affect the structure or function of the human body.

When punicalagin or punicalagin-containing plant extract and cannabis or cannabinoids are administered together for the purpose of curing, treating, alleviating, mitigating or preventing a disease or condition which can be alleviated, cured, mitigated, prevented and/or treated by cannabis or any one or more cannabinoids, an enhanced effect is provided, exceeding the effect, e.g., beneficial effect, exerted by administration of at least one cannabinoid, cannabis or a cannabis plant extract or essential oil alone, without punicalagin or a punicalagin-containing plant extract.

Likewise, when punicalagin or punicalagin-containing plant extract and cannabis or at least one cannabinoid such as for example CBD are administered together for the purpose of curing, treating, alleviating, mitigating or preventing a disease or condition which can be treated, alleviated, cured, mitigated, and/or prevented by punicalagin or punicalagin-containing plant extract, a synergistic effect is provided, exceeding the effect, exerted by administration to a subject in need thereof of punicalagin or punicalagin-containing plant extract without cannabis or at least one cannabinoid (see infra and Example 1).

In some embodiments, the at least one cannabinoid is CBD. In some embodiments, co-administration of punicalagin or punicalagin-containing plant extract and at least one cannabinoid and/or cannabis extract results in an additive effect while treating or alleviating a disease or condition effected or treatable both by punicalagin or punicalagin-containing plant extract and cannabinoids/cannabis.

In some embodiments, co-administration of punicalagin or punicalagin-containing plant extract and at least one cannabinoid such as CBD and/or cannabis extract results in a potentiating effect while treating or alleviating a disease or condition effected or treatable both by punicalagin or punicalagin-containing plant extract and cannabinoids/cannabis. Namely, one active agent, e.g., punicalagin or punicalagin-containing plant extract potentiates the therapeutic effect of the other active agent, e.g., at least one cannabinoid and/or cannabinoids potentiate the therapeutic effect of punicalagin or punicalagin-containing plant extract.

Embodiments featuring“co-administration” of punicalagin or punicalagin-containing plant extract and at least one cannabinoid or cannabis include embodiments wherein punicalagin or punicalagin-containing plant extract and at least one cannabinoid, cannabis extract and/or cannabis essential oil are administered or consumed simultaneously, and embodiments of consecutive administration, wherein one active agent, e.g., punicalagin or punicalagin-containing plant extract, punicalagin or punicalagin-containing plant extract-containing extract or punicalagin or punicalagin-containing plant extract or essential oil is administered followed or preceded by a second active agent e.g., at least one cannabinoid, cannabis extract or cannabis essential oil.

The at least one cannabinoid and punicalagin may be administered together at the same time, or, alternatively, they may be administered or consumed separately according to a predetermined regimen, for example, before, together with and/or after administration or consumption of punicalagin or punicalagin-containing plant extract.

Co-administration of punicalagin or punicalagin-containing plant extract at least one cannabinoid and/or cannabis may be effected by providing to a subject in need thereof a composition as described herein formulated as a single unit dose form essentially comprising punicalagin or punicalagin-containing plant extract, punicalagin or punicalagin-containing plant extract-containing extract and/or punicalagin or punicalagin-containing plant extract-containing essential oils, and at least one cannabinoid, cannabis extract and/or cannabis oil.

Alternatively, or additionally, co-administration of punicalagin or punicalagin-containing plant extract and at least one cannabinoid and/or cannabis is effected by providing to a subject in need thereof two or more units of dosage form, at least one of which comprises punicalagin or punicalagin-containing plant extract, punicalagin or punicalagin-containing plant extract-containing extract and/or punicalagin or punicalagin-containing plant extract-containing essential oils, and at least one dosage form comprises cannabis extract, cannabis essential oil, and/or at least one cannabinoid.

Diseases and conditions treatable and/or alleviated by co-administration of punicalagin or punicalagin-containing plant extract or punicalagin-containing essential oil, and at least one cannabinoid and/or cannabis and/or cannabis extract and/or cannabis essential oil, include, but are not limited to, a gastro-enterologic, an inflammatory, an autoimmune, a neurodegenerative, an oncologic, a cardiovascular, or an infectious (e.g., viral, bacterial, fungal) disease or disorder.

Non-limiting examples of medical conditions treatable or alleviated by the composition described herein include nausea, appetite loss and pain associated with cancer and chemotherapy; nausea, appetite loss, pain and wasting associated with AIDS; toothache; arthritis and rheumatism; glaucoma; scurvy; migraine; muscle spasticity associated e.g., with multiple sclerosis and paralysis; alcohol and narcotics withdrawal; stress; depression; asthma; neurological disorders such as Tourette syndrome, Cervical dystonia or epileptic seizures; dementia; dysmenorrhea; anxiety disorders; diabetes; diarrhea; neuropathic pain; chronic pain; autoimmune diseases; skin diseases such as psoriasis, dermatitis and swimmer’s eczema; neurodegeneration and neurodegenerative disorders such as Alzheimer’s disease, Huntington disease and Parkinson’s disease; Lyme disease; post-traumatic stress disorder; inflammation such as liver inflammation; mental diseases such as schizophrenia; post-traumatic stress disorder (PTSD) and pain associated therewith; malaria; vasoconstriction, allergy; edema colitis; heart diseases; painful spasms; fibromyalgia and pain associated therewith; sexual disfunction; and other medical conditions described throughout the specification.

In some embodiments, the condition treated by co-administration of punicalagin and at least one cannabinoid is sepsis, a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs.

In some embodiments, there is provided a method of treatment, prevention or amelioration of a gastro-enteric disease by administration to a subject in need thereof a therapeutically effective amount of a FDC composition of this invention. The gastro-enteric disease is selected from the group consisting of irritable bowel disease, Crohn's disease, colitis, irritable bowel syndrome, and acute or chronic pancreatitis. In some embodiments, there is provided a method of treatment, prevention or amelioration of sepsis by administrating to a subject in need thereof a therapeutically effective amount of a composition of this invention.

In some other embodiments, there is provided a method of treatment, prevention or amelioration of a condition amenable to treatment, prevention or amelioration by administration to a patient in need thereof of a composition comprising therapeutically effective amounts of at least one cannabinoid and punicalagin.

In some embodiments, there is provided a method of treatment, prevention or amelioration of a gastric disease or of sepsis by administration to a subject in need thereof of therapeutic amounts of at least one cannabinoid and punicalagin or punicalagin-containing plant extract, wherein the at least one cannabinoid is CBD.

In some embodiments, the disease or condition treated by co -administration of punicalagin and at least one cannabinoid is necrotizing soft tissue infections (NSTI).

NSTIs are aggressive severe soft tissue infection that cause rapid and widespread infection and necrosis of the skin and soft tissues and are highly lethal. NSTIs include necrotizing cellulitis, adipositis, fasciitis and myositis/myonecrosis and have significant potential for extensive soft tissue and limb loss. Co-administration of punicalagin or punicalagin-containing plant extract and cannabinoids and/or cannabis (e.g., cannabis extract or cannabis oil) optionally together with surgical debridement and/or early appropriate antibiotic treatment can provide a successful outcome and clinical cure of NSTI.

In some embodiments, the disease or condition treated by co -administration of punicalagin and at least one cannabinoid is acute and chronic pancreatitis.

In some embodiments, the condition treated by co-administration of punicalagin and at least one cannabinoid is opioid addiction.

Co-administration of punicalagin or punicalagin-containing plant extract (e.g., purified form plant material), or essential oil, and at least one cannabinoid and/or cannabis extract or cannabis oil can provide a significant relief in opioid addiction.

In some embodiments, the disease or condition treated by co -administration of punicalagin and at least one cannabinoid is inflammatory bowel disease (IBD).

Inflammatory bowel disease represents a group of intestinal disorders that cause prolonged inflammation of the digestive tract. Many diseases are included in this IBD umbrella term. The two most common diseases are ulcerative colitis and Crohn’s disease. Crohn’s disease can cause inflammation in any part of the digestive tract. However, it mostly affects the tail end of the small intestine. Ulcerative colitis involves inflammation of the large intestine. Co-administration of punicalagin or punicalagin-containing plant extract (e.g., purified form plant material or chemically synthesized), punicalagin or punicalagin-containing plant extract-containing extract and/or punicalagin or punicalagin-containing plant extract-containing essential oil, and cannabinoids and/or cannabis (e.g., cannabis extract or cannabis oil) can e.g., alleviate one or more symptoms of IBD such as diarrhea, stomach pain, bleeding ulcers and weight loss.

In some embodiments, the disease or condition treated by co -administration of punicalagin or punicalagin-containing plant extract and at least one cannabinoid is irritable bowel syndrome (IBS).

Irritable bowel syndrome (IBS) is a common disorder that affects the large intestine (colon), with worldwide prevalence rates estimated in the range of 10%-15% of the population. Irritable bowel syndrome commonly causes cramping, abdominal pain, bloating, gas, alternating periods of persistent diarrhea or constipation and mucus in the stool. IBS is a chronic condition, however, unlike ulcerative colitis and Crohn's disease, which are forms of inflammatory bowel disease, IBS doesn't cause changes in bowel tissue or increases the risk of colorectal cancer. Co-administration of punicalagin or punicalagin-containing plant extract or essential oil, and at least one cannabinoid and/or cannabis extract or cannabis oil may show a synergistic effect in the treatment of IBS, e.g., in alleviating one or more symptoms of IBS such as diarrhea, abdominal pain, bloating, or gas.

For example, a composition comprising punicalagin and at least one cannabinoid such as CBD, can be formulated as a nutraceutical, a food supplement or wellness product for treating IBS. Such a product may be a generally regarded as safe (GRAS) product by global regulatory authorities and would not need a pharmaceutical regulatory process as an Rx product in order to reach the market immediately.

In a specific embodiment, the disease or condition treated by co-administration of punicalagin or punicalagin-containing plant extract and at least one cannabinoid and/or cannabis (e.g., cannabis extract or oil) is non-alcoholic fatty liver disease (NAFLD).

Non-alcoholic fatty liver disease describes a range of conditions caused by a build-up of fat within liver cells. It is very common and in many cases is linked to being obese or overweight. In some people, the build-up of fat in the liver can lead to serious liver disease. All people with non alcoholic fatty liver disease have an increased risk of developing cardiovascular problems such as heart attacks and stroke. Co-administration of punicalagin and at least one cannabinoid can alleviate or decrease accumulation of fat in the liver.

In some embodiments, the disease or condition treated by co -administration of punicalagin or punicalagin-containing plant extract and at least one cannabinoid and/or cannabis (e.g., cannabis extract or cannabis oil) is cancer, for example, a brain tumor such as glioma, the most common and most aggressive of the primary brain tumors.

The punicalagin and at least one cannabinoid containing compositions described herein may have a direct anti-cancer effect, namely may induce the selective apoptosis and necrosis of cancer cells and thus work as a direct anti-cancer dmg.

In addition, the punicalagin or punicalagin-containing plant extract and cannabinoids and/or cannabis (e.g. cannabis extract or cannabis oil) containing compositions described herein may have enhancement effects as add-on therapy to existing, or under development, cancer dmgs, including chemotherapy drugs, targeted anti-cancer dmgs and immune oncology dmgs such as programmed death 1 (PD-l) inhibitors and others. In each case, the combined therapy of a composition as described herein together with the specific anti-cancer dmg may increase the over-all efficacy of the treatment and, furthermore, increase the response rate of patients to the therapy. For example, an immune -oncology therapy that has a typical low response rate of patients, may be effective in a higher percentage of the patients when administered together with a combined cannabinoids- punicalagin composition.

Cannabinoids act as potentiators of the immune system and may have very high potential as primary anti-cancer therapies and as enhancers of common approved anticancer dmgs. A dual or combined therapy comprising an immune -oncology (10) dmg (e.g., Keytmda, by Merck), which is considered as the one of the leading anti-cancer therapies in today’s oncology clinics, and a composition comprising punicalagin or punicalagin-containing plant extract and at least one cannabinoid as described herein, allows achieving higher efficacy with lower dosages of IO dmgs, and reduced toxic effects for patients. Such a combined therapy can even totally eradicate the tumors of certain patients.

Treatment of atherosclerosis with CBD and punicalagin

In some embodiments, there is provided a method of treatment of atherosclerosis with a composition comprising at least one cannabinoid and punicalagin.

In some other embodiments, the at least one cannabinoid in the above composition is cannabidiol (CBD). Example 1 below details the results of a pre-clinical study related to the treatment of atherosclerosis with CBD and punicalagin.

This study uncovered the effect of CBD + punicalagin on the local aorta pro-inflammatory IL-6 cytokine levels.

Without wishing to be linked to theory, the inventor believes that the local aorta pro- inflammatory IL-6 cytokine levels are linked to the atherosclerotic disease severity within the aorta.

The study assessed the efficacy of CBD, punicalagin and a combination of CBD and punicalagin in the local aorta pro -inflammatory IL-6 cytokine level lowering and thence the potential for treatment of atherosclerosis.

The preclinical model of choice was ApoE knockout mice fed with high fat diet. Local aorta pro-inflammatory IL-6 cytokine levels linked to disease severity within the aorta were measured as the study readout.

Studv treatment groups:

1. Healthy group: C57BL6 mice fed with normal diet - no treatment.

2. Vehicle group - ApoE-/- (KO) mice fed with high fat diet - no treatment.

3. CBD group - ApoE-/- (KO) mice fed with high fat diet - 50mg/Kg CBD.

4. Punicalagin group - ApoE-/- (KO) mice fed with high fat diet - lOmg/Kg punicalagin.

5. Combination group ApoE-/- (KO) mice fed with high fat diet - 50mg/Kg CBD + lOmg/Kg punicalagin.

Study readout

Following 4 weeks of treatment with the study combinations (3 times per week via gavage), the mice were perfused with PBS and sacrificed. The aorta was then harvested and local biopsies were taken for measurement of the pro-inflammatory IL-6 cytokine levels within the aorta using Multiplex ELISA.

Study results

The average local aorta IL-6 pro-inflammatory cytokine level in the healthy mice control group was measured at 194 pg/ml - this is the low baseline cytokine level in healthy animals that are not ApoE knockouts and are fed with normal diet - without blood vessel inflammation related to advanced atherosclerotic plaque formation.

The same measurement for the ApoE KO high fat diet vehicle (no treatment) mice group yielded a result of 3,366pg/ml of IL-6 in average, indicating a relative average increase of 3,l72pg/ml in the local aorta concentration levels of the pro-inflammatory IL-6 cytokine as compared to the healthy group - a clear indication for the advanced atherosclerotic inflammatory conditions in the blood vessels of the ApoE knockout mice that were fed with a high fat diet.

Same measurement for the CBD alone treatment group has yielded a result of 2,686pg/ml IL-6 levels in average - representing a decrease of 680pg/ml (21.4%) relative to the vehicle group.

The punicalagin alone treatment group was measured at an average level of 3,028pg/ml - a decrease of 338pg/ml (10.66%) relative to the vehicle group.

Finally, the average local aorta pro -inflammatory cytokine IL-6 levels in the CBD + punicalagin combination treatment group was measured as 822 pg/ml only - a substantial decrease of 2,544 pg/ml (80.2%) in the IL-6 cytokine levels relative to the vehicle group (Figure 1).

Conclusions

While the CBD treatment alone was able to prevent 21.4% of the IL-6 elevation effect due to the high fat diet in the ApoE knockout mice and the punicalagin treatment alone was able to prevent 10.66% of this same effect, the combined treatment of both compounds (with the same doses) was able to prevent as much as 80.2% of the IL-6 elevation effect (Figure 2).

This result demonstrates a clear synergistic therapeutic effect of the CBD and Punicalagin when administered together as a combination therapy, since the ameliorating therapeutic effect of the combination treatment is stronger than the sum of the effects of the two constituents when administered separately (80.2% > 21.4% + 10.66%).

This result demonstrates the potential superior and synergistic therapeutic efficacy that can be achieved by using these constituents as a combined atherosclerosis therapy as compared to each of them separately.

Methods of treatment targeted against the nro-inflammatorv cytokine IL-6

As the punicalagin combination with at least one cannabinoid (CBD) has shown exceptional activity as a down regulator of IL-6 in the study model (see Example 1), the punicalagin/cannabinoid combination has the potential for treatment, prevention or alleviation of other medical indications benefiting from the down regulation of the IL-6 cytokine. These medical indications are selected from rheumatoid arthritis, systemic juvenile idiopathic arthritis, Castleman’s disease, neuromyelitis optica, giant cell arteritis and cytokine release syndrome.

In some embodiments, there is provided a composition comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin and a earner. In some other embodiments, there is provided a composition comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin and a carrier, wherein the at least one cannabinoid and the punicalagin are essentially pure, having an assay of at least 92% w/w, at least 95% w/w or at least 98% w/w.

According to some embodiments, there is provided a composition comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin and a carrier, wherein the at least one cannabinoid is a component of a cannabis essential oil or extract and punicalagin is a component of a punicalagin-containing essential oil or extract.

According to some other embodiments, there is provided a composition comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin and a carrier, wherein the at least one cannabinoid is essentially pure having an assay of at least 92% w/w, at least 95% w/w or at least 98% w/w and punicalagin is a component of a punicalagin-containing plant extract or essential oil.

According to some other embodiments, there is provided a composition comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin and a carrier, wherein the at least one cannabinoid is a component of a cannabis essential oil or extract and punicalagin is an essentially pure plant isolate or synthetic punicalagin, having an assay of at least 92% w/w, at least 95% w/w or at least 98% w/w.

According to some embodiments, there is provided a composition comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin and a carrier, wherein punicalagin is a component of pomegranate standardized extract comprising at least 30% punicalagin and optionally at least 25% ellagic acid and other ellegitannin complexes.

In some embodiments, the at least one cannabinoid in the compositions of this invention is selected from the group consisting of tetrahydrocannabinol (THC), iso-tetrahydrocannabinol-type (iso-THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabinol (CBN), cannabinolic acid (CBNA), cannabinol methyl ether (CBNM), cannabinol-C4 (CBN-C4), cannabinol-CZ (CBN-C2), cannabiorcol (CBN-C1), cannabinodiol (CBND), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerolic acid monomethyl ether (CBGAM), cannabigerol monomethyl ether (CBGM), cannabigerovarinic acid (CBGVA), cannabichromene (CBC), cannabichromanon (CBCN), cannabichromenic acid (CBCA), cannabichromevarin (CBCV), cannabichromevarinic acid (CBCVA), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabielsoin (CBE), cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), cannabigerovarin (CBGV), cannabidiolic acid (CBDA), cannabidiol monomethyl ether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic acid (CBDVA), and cannabidiorcol (CBD-C1), cannabicyclol (CBL), cannabicyclolic acid (CBLA), cannabicyclovarin (CBLV), cannabitriol, cannabitriolvarin (CBTV), ethoxy-cannabitiolvarin (CBTVE), cannabivarin (CBV), cannabidivarin (CBVD), cannabitriolvarin (CBTV), ethoxy- cannabitiolvarin (CBTVE), cannabifuran (CBF), dehydrocannabifuran (DCBF), and cannabiripsol (CBR), pharmaceutically acceptable salts thereof, solvates, metabolites, metabolic precursors, isomers, derivatives and mixtures thereof.

In some other embodiments, the compositions of this invention may further comprise at least one additional ingredient selected from a phytochemical, an essential oil, a carrier oil, an antibacterial agent, an antioxidant, an anti-inflammatory agent, an anti-viral agent, an antifungal agent, an anti-microbial agent, a chemotherapeutic agent, an immuno-oncologic (10) agent, an immune-apoptosis inducing agent, an anti-diarrheal agent, an anti-histamine, a probiotic, a vitamin, a colorant, a buffer, an emulsifier, a sunscreen, a moisturizer, an analgesic agent, an anti-depressant agent, a skin nutrient, a medicinal herbal extract, a flavor, a flower essence, a protein, a lubricant, a buffering agent, a bulking agent and mixtures thereof.

According to some embodiments, the at least one cannabinoid in the compositions of this invention is selected from CBD, its isomers, derivatives and mixtures thereof.

According to some other embodiments, the at least one cannabinoid in the compositions of this invention is selected from THC, its isomers, derivatives and mixtures thereof.

In some embodiments, there is provided a dosage form formulated for oral, topical, parenteral, sublingual, buccal, rectal, intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, intrapleural, intratracheal, subcutaneous, transdermal, intradermal, or intranasal administration, or for inhalation, preferably for oral or sublingual administration to a patient in need thereof, comprising a therapeutically effective amount of a composition of this invention, for use in treatment, alleviation, or prevention of a disease, disorder or medical condition.

In some other embodiments, there is provided a kit of two pharmaceutical dosage forms and instructions for use, the first dosage form comprising a therapeutically effective amount of punicalagin and a carrier, and the second dosage form comprising a therapeutically effective amount of at least one cannabinoid and a carrier, for concomitant or sequential administration in either order to a subject in need thereof, for use in treatment, alleviation, or prevention of a disease, disorder or medical condition.

In some embodiments, there is provided a method of treatment, prevention or amelioration of a disease, disorder or medical condition, comprising the administration to a subject in need thereof of a therapeutically effective amount of any one of the compositions or dosage forms of this invention comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin, and a carrier, thereby treating, preventing or ameliorating the disease, disorder or medical condition.

In some other embodiments, there is provided a method of treatment, prevention or amelioration of a disease, disorder or medical condition, comprising the administration to a subject in need thereof of a therapeutically effective amount of any one of the compositions or dosage forms of this invention comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin and a carrier, wherein the disease, disorder or medical condition is selected from a cardiovascular disease, atherosclerosis, blood vessel calcification, cerebral infarction, a gastro-enterologic disease, an autoimmune disease, an immunodeficiency disease, a neurodegenerative disease, neuronal damage, neuro-inflammation, an oncologic disease, a mental or psychiatric disease, a skin disease, a microbial, viral, bacterial or fungal infection, a blood vessels disease, cancer, hepatitis, hepatoma, headaches, fever, cough, cold, inflammation, allergy, vertigo, body aches, digestion disorders, obesity, sepsis, depression, glaucoma, pain, malaria, addiction, anxiety, depression, water retention, diarrhea, blood vessel dilation, nausea, appetite loss and pain associated with cancer and chemotherapy, nausea, appetite loss, pain and wasting associated with AIDS, toothache, arthritis, rheumatism, glaucoma, migraine, scurvy, muscle spasticity, alcohol and narcotics withdrawal, stress, asthma, Tourette syndrome, cervical dystonia, epileptic seizures, dementia, dysmenorrhea, diabetes, diabetes-related retinopathy, neuropathic pain, chronic pain, psoriasis, dermatitis, swimmer’s eczema, Alzheimer’s disease, Huntington disease, Parkinson’s disease, Lyme disease edema, liver inflammation, schizophrenia, colitis, painful spasms, fibromyalgia, sexual disfunction, post-traumatic stress disorder (PTSD), sepsis, necrotizing soft tissue infections (NSTI), acute or chronic pancreatitis, inflammatory bowel disease (IBD), non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS).

In some embodiments, there is provided a method of treatment, prevention or amelioration of a disease, disorder or medical condition, comprising the administration to a subject in need thereof of a therapeutically effective amount of any one of the compositions or dosage forms of this invention comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin and a carrier, wherein the disease, disorder or medical condition is atherosclerosis and said method is beneficial for reducing inflammation in atherosclerotic plaques, thus rendering them less vulnerable to empt and clog small blood vessels in the heart or brain.

In some other embodiments, there is provided a method of treatment, prevention or amelioration of a disease, disorder or medical condition, comprising the administration to a subject in need thereof of a therapeutically effective amount of any one of the compositions or dosage forms of this invention comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin, and a carrier, wherein the disease, disorder or medical condition is atherosclerosis or blood vessel calcification and said method is beneficial for reducing Reactive Oxygen Species (ROS) presence and reactive oxidative stress in atherosclerotic lesions, thus preventing further damage to vessel tissue and accumulation of debris, calcium, inflammatory agents and cells in lesions.

According to some embodiments, there is provided a method of treatment, prevention or amelioration of a disease, disorder or medical condition, comprising the administration to a subject in need thereof of a therapeutically effective amount of any one of the compositions or dosage forms of this invention comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin, and a carrier, wherein the disease, disorder or medical condition is cerebral infarction or stroke and said method is beneficial in reducing infarct size and increasing blood flow.

According to some other embodiments, there is provided a method of treatment, prevention or amelioration of a disease, disorder or medical condition, comprising the administration to a subject in need thereof of a therapeutically effective amount of any one of the compositions or dosage forms of this invention comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin, and a carrier, wherein the disease, disorder or medical condition is caused by inflammation or an inflammatory process and is selected from Alzheimer's disease, ankylosing spondylitis, arthritis (osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis, asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus erythematosus (SLE), nephritis, Parkinson's disease and ulcerative colitis. In some embodiments, there is provided a method of treatment, prevention or amelioration of a disease, disorder or medical condition, comprising the administration to a subject in need thereof of a therapeutically effective amount of any one of the compositions or dosage forms of this invention comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin, and a carrier, wherein the disease, disorder or medical condition is caused by inflammation or an inflammatory process caused by the pro- inflammatory cytokine IL-6 and is selected from atherosclerosis, rheumatoid arthritis, systemic juvenile idiopathic arthritis, Castleman’s disease, neuromyelitis optica, giant cell arteritis and cytokine release syndrome.

According to some embodiments, there is provided a method of treatment, prevention or amelioration of a disease, disorder or medical condition, comprising the administration to a subject in need thereof of a therapeutically effective amount of any one of the compositions or dosage forms of this invention comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin, and a carrier, wherein the disease, disorder or medical condition is selected from myocardial, liver or renal ischemic / reperfusion injury and the method is beneficial by providing protection.

According to some other embodiments, there is provided a method of treatment, prevention or amelioration of a disease, disorder or medical condition, comprising the administration to a subject in need thereof of a therapeutically effective amount of any one of the compositions or dosage forms of this invention comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin, and a carrier, wherein co administration of therapeutically effective amounts of at least one cannabinoid and punicalagin results in a therapeutic effect selected from a synergistic effect, an additive effect, a potentiating effect and any combination thereof.

In some embodiments, there is provided a method of treatment, prevention or amelioration of a disease, disorder or medical condition, comprising the administration to a subject in need thereof of a therapeutically effective amount of any one of the compositions or dosage forms of this invention comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin, and a carrier, wherein the composition comprising at least one cannabinoid and punicalagin exhibits a synergistic therapeutic effect when compared to the therapeutic effect of the at least one cannabinoid and of punicalagin respectively administered to a patient in need thereof separately in a similar amount. According to some embodiments, there is provided a method of treatment, prevention or amelioration of a disease, disorder or medical condition, comprising the administration to a subject in need thereof of a therapeutically effective amount of any one of the compositions or dosage forms of this invention comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin, and a carrier for treating, preventing or alleviating a disease, disorder or medical condition, comprising administering concomitantly or sequentially in either order two pharmaceutical dosage forms, the first dosage form comprising a therapeutically effective amount of punicalagin and a carrier, and the second dosage form comprising a therapeutically effective amount of at least one cannabinoid and a carrier.

In some embodiments, there is provided an article of manufacture comprising any one of the compositions of this invention, wherein the article of manufacture is in the form of a cosmeceutical, a nu tricosmetic, a body care product, a personal hygiene product or a cosmetic product selected from a body lotion, a soap, a body wash, a moisturizer, a self-tanner, a hand cream, a body scmb, a sunscreen, a bath product, a toothpaste, a soap, a shampoo, a mouthwash, a deodorant, an antiperspirant, a shaving soap, an anti-wrinkle product, a moisturizing cream, a face mask, a makeup and a lipstick.

According to a specific embodiment, the subject treated with the composition is a human being, though veterinary indications are also contemplated herein.

The subject may suffer from the disease or be at risk of having it. The subject may be of any gender or age.

Definitions

Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases“ranging/ranges between” a first indicate number and a second indicate number and“ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

The dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as“10 pm” is intended to mean“about 10 pm”.

As used herein, numerical ranges preceded by the term“about” should not be considered to be limited to the recited range. Rather, numerical ranges preceded by the term“about” should be understood to include a range accepted by those skilled in the art for any given element in microcapsules or formulations according to the present invention.

The term“about” as used herein means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example,“about” can mean a range of up to 10%, more preferably up to 5%, and still more preferably up to 1% of a given value. Where particular values are described in the application and claims, unless otherwise stated, the meaning of the term“about” is within an acceptable error range for the particular value.

The terms "comprise", "comprising", "includes", "including",“having” and their conjugates mean "including but not limited to".

The term“consisting of’ means“including and limited to”.

The term "consisting essentially of" means that the composition, method or microcapsules may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

An FDC dmg, also known as combination dmg, is a fixed-dose combination, that includes two or more active pharmaceutical ingredients (APIs), combined in a single dosage form, which is manufactured and distributed in fixed doses.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non-limiting fashion.

Generally, the nomenclature used herein and the laboratory procedures utilized in the present invention include chemical, molecular and biochemical, techniques. Such techniques are thoroughly explained in the literature. General references are provided throughout this document. The procedures therein are believed to be well known in the art and are provided for the convenience of the reader. All the information contained therein is incorporated herein by reference.

Materials and Methods

(i) Isolation and purification of punicalagin from pomegranate (Punica granatum L.) husk

Punicalagin is separated from pomegranate husk by high-speed counter-current chromatography (HSCCC) in over 92% purity (Jingjing Lu et al. J. of Chromatography B, v. 857, Issue 1, 15 Sep. 2007, pp. 175-179).

(ii) Cannabis oil and purified cannabinoids

Cannabis oil, cannabis extracts, and cannabinoids used in accordance with the invention are either purchased or prepared using chemical, molecular and biochemical techniques well taught and known to those skilled in the art. In an exemplary embodiment, cannabis extracts and cannabinoids are obtained using procedures taught in U.S. Patent Publication No. 2016/0346339, hereby incorporated by reference in its entirety.

EXAMPLE 1

Atherosclerosis - preclinical study results

Synopsis

The efficacy of CBD, punicalagin and a combination of CBD and punicalagin in the treatment of atherosclerosis was assessed. The preclinical model of choice was ApoE knockout mice fed with high fat diet. Local aorta pro-inflammatory IL-6 cytokine levels linked to disease severity within the aorta were measured as the study readout.

Study protocol

Animals:

ApoE-/- (KO) male mice (Jackson Laboratories (Bar Harbor, ME)).

The ApoE knockout mice were fed with a high-fat/high-cholesterol diet (HFD, 0.2% total cholesterol, 43% calories from fat; Harlan Israel) ad libitum beginning at 8 weeks of age, for a period of 8 weeks.

C57BL6 mice were used as healthy control.

All mice were kept in the SPF facility under sterile conditions and each group consisted of 10 mice.

Study treatments were administrated via gavage (oral administration) 3 times per week starting on week 9 for 4 weeks.

Studv treatment groups:

1. Healthy group: C57BL6 mice fed with normal diet - no treatment.

2. Vehicle group - ApoE-/- (KO) mice fed with high fat diet - no treatment.

3. CBD group - ApoE-/- (KO) mice fed with high fat diet - 50mg/Kg CBD.

Study readout

Study results

Linally, the average local aorta pro -inflammatory cytokine IL-6 levels in the CBD + punicalagin combination treatment group was measured as 822 pg/ml only - a substantial decrease of 2,544 pg/ml (80.2%) in the IL-6 cytokine levels relative to the vehicle group (Ligure 1).

Conclusions

While the CBD treatment alone was able to prevent 21.4% of the IL-6 elevation effect due to the high fat diet in the ApoE knockout mice and the punicalagin treatment alone was able to prevent 10.66% of this same effect, the combined treatment of both compounds (with the same doses) was able to prevent as much as 80.2% of the IL-6 elevation effect (Ligure 2).

This result demonstrates the potential superior and synergistic therapeutic efficacy that can be achieved by using these constituents as a combined atherosclerosis therapy as compared to each of them separately. EXAMPLE 2

Chronic IBD model (prophetical)

Study of the efficacy of CBD, punicalagin and CBD + punicalagin combination for the treatment of IBD. Chosen preclinical model - IL10 Knockout mice induced with Piroxicam. This NSAID gives a similar Thl directed inflammation like the spontaneous colitis. This model is up and mnning within 3 weeks.

Study protocol:

Colitis is induced in 10 weeks old male C57BL/6 mice (Harlan laboratories, Israel) using Piroxicam

Dosage: CBD - 50mg/kg and separately lOmg/Kg Punicalagin and combination thereof. Study combinations will be administrated via gavage 3 times per week for 14 weeks.

Study arms: Control (saline), CBD, Punicalagin, CBD + Punicalagin combination. Each group will include 10 mice. Total of 40 mice. Body weight will be monitored every other day.

After 14 weeks of treatment colitis severity will be assessed by colonoscopy scored using the Murine Endoscopic Index of Colitis (MEICS) and then animals will be sacrificed.

All MEICS scoring was determined based on three impartial assessments.

The length of the entire colon from cecum to anus will be measured.

Small segments of the colon will be taken for histologic and immunohistochemistry evaluation.

Colon samples will be homogenized to assess cytokines by IL-6 and TNFa ELISA kits (R&D Systems, USA).

EXAMPLE 3

A Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Efficacy and Safety of CBD + Punicalagin therapy in Adults with Pain Due to Osteoarthritis of the Knee

(prophetical)

Objectives:

The primary trial objective is to evaluate the efficacy of CBD + Punicalagin versus

placebo in improving knee pain, when applied to patients suffering from OA of the knee. The secondary trial objectives include: evaluation of the safety of CBD + Punicalagin when administered to patients suffering from OA of the knee, evaluation of the

efficacy of CBD + Punicalagin and placebo on stiffness and function when

applied to patients suffering from OA of the knee and evaluation of responder status defined by the Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society

International (OMERACT-OARSI) criteria.

Secondary exploratory objectives are to: analyze the effect, if any, of CBD + Punicalagin on intra- articular inflammatory growth markers in a subset of patients and to assess

any radiological changes visible in MRI.

Methods:

Randomized, placebo-controlled, double -blind study with a 28 days screening period for each patient followed by a 12 weeks participation period. A total of 100 patients, 50 patients per study arm, with osteoarthritis knee pain will be randomized 1 :1 across the 2 study arms: CBD +

Punicalagin and placebo.

A subset of patients, approximately 20 total patients, randomized 1 : 1 from the treatment and placebo arms will undergo clinical laboratory testing and a 1 -2mL aspiration of synovial fluid of the index knee at Baseline and Week 12, and an MRI of the index knee at Baseline and Week 12.

The clinical effects of treatment on OA pain will be evaluated during clinic visits at 6 and

12 weeks, and telephone contacts at 2, 4, 8 and 10 weeks, using the Western Ontario and

McMaster Universities Arthritis Index (WOMAC®) osteoarthritis Index 3.1 , and the Patient’s Global Assessment of disease severity (PGA). The WOMAC® is a validated pain scoring system and sets the standard for the patient response. In order not to bias the collection of data, only questions from the validated WOMAC pain scale will be asked of patients.

Clinical meaningfulness will be determined by the end results of this trial, specifically by the apparent clinical benefit versus any adverse events or any increased apparent risk. Safety will be assessed by recording adverse events and physical examination and vitals (Baseline, Weeks 6 and 12).

EXAMPLE 4

Collagen-induced Rheumatoid Arthritis Model (prophetical)

Study of the efficacy of CBD, punicalagin and CBD + punicalagin combination for the treatment of rheumatoid arthritis (RA). Chosen preclinical model - collagen-induced rheumatoid arthritis (CIA) following immunization with type II collagen. The CIA model has been widely studied as a model of arthritis, largely on the basis of the pathological similarities between CIA and RA. Thus, both RA and CIA exhibit similar patterns of synovitis, pannus formation, erosion of cartilage and bone, fibrosis, and loss of joint mobility. Study protocol:

Collagen-induced rheumatoid arthritis will be induced in DBA/l J mice by immunization with Bovine Collagen Emulsion in CFA, or in C57BL/6J mice by immunization with type II chicken collagen, via a daily injection into the tail for 8 weeks.

Treatment arms: Dosage: CBD - 50mg/kg and separately lOmg/Kg Punicalagin and combination thereof. Study combinations will be administrated via gavage 3 times per week for 8 weeks.

RA scoring:

Severity of RA symptoms will be measured weekly until day 21 and twice a week after day 21 by measurement of paw thickness.

An arthritis score will be assigned to each paw with the following criteria:

0: Normal, no inflammation or redness

1 : Redness and swelling in one digit

2: Redness and swelling in more than one digit or redness and swelling in one digit and ankle and wrist joint.

3: Redness and swelling present in all digits and joints

After 8 weeks of treatment animals will be sacrificed and joint tissue samples will be collected and homogenized to assess cytokines levels (including IL-4, IL-6, TNFa and others)

Claims

WHAT IS CLAIMED IS:

1. A composition comprising a therapeutically effective amount of at least one cannabinoid, a therapeutically effective amount of punicalagin, and a carrier.

2. The composition of claim 1 , wherein the at least one cannabinoid and the punicalagin are essentially pure, having an assay of at least 92% w/w, at least 95% w/w or at least 98% w/w.

3. The composition of claim 1, wherein the at least one cannabinoid is a component of a cannabis essential oil or extract and punicalagin is a component of a punicalagin-containing essential oil or extract.

4. The composition of claim 1, wherein the at least one cannabinoid is essentially pure having an assay of at least 92% w/w, at least 95% w/w or at least 98% w/w and punicalagin is a component of a punicalagin-containing plant extract or essential oil.

5. The composition of claim 1, wherein the at least one cannabinoid is a component of a cannabis essential oil or extract and punicalagin is an essentially pure plant isolate or synthetic punicalagin, having an assay of at least 92% w/w, at least 95% w/w or at least 98% w/w.

6. The composition according to claim 1, wherein punicalagin is a component of pomegranate standardized extract comprising at least 30% punicalagin and optionally at least 25% ellagic acid and other ellegitannin complexes.

7. The composition according to any one of claims 1-6, wherein the at least one cannabinoid is selected from the group consisting of tetrahydrocannabinol (THC), iso-tetrahydrocannabinol- type (iso-THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabinol (CBN), cannabinolic acid (CBNA), cannabinol methyl ether (CBNM), cannabinol-C4 (CBN-C4), cannabinol-CZ (CBN-C2), cannabiorcol (CBN-C1), cannabinodiol (CBND), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerolic acid monomethyl ether (CBGAM), cannabigerol monomethyl ether (CBGM), cannabigerovarinic acid (CBGVA), cannabichromene (CBC), cannabichromanon (CBCN), cannabichromenic acid (CBCA), cannabichromevarin (CBCV), cannabichromevarinic acid (CBCVA), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabielsoin (CBE), cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), cannabigerovarin (CBGV), cannabidiolic acid (CBDA), cannabidiol monomethyl ether (CBDM), cannabidiol- C4 (CBD-C4), cannabidivarinic acid (CBDVA), and cannabidiorcol (CBD-C1), cannabicyclol (CBL), cannabicyclolic acid (CBLA), cannabicyclovarin (CBLV), cannabitriol, cannabitriolvarin (CBTV), ethoxy-cannabitiolvarin (CBTVE), cannabivarin (CBV), cannabidivarin (CBVD), cannabitriolvarin (CBTV), ethoxy-cannabitiolvarin (CBTVE), cannabifuran (CBF), dehydrocannabifuran (DCBF), and cannabiripsol (CBR), pharmaceutically acceptable salts thereof, solvates, metabolites, metabolic precursors, isomers, derivatives and mixtures thereof.

8. The composition according to any one of claims 1-7, further comprising at least one additional ingredient selected from a phytochemical, an essential oil, a carrier oil, an antibacterial agent, an antioxidant, an anti-inflammatory agent, an anti-viral agent, an antifungal agent, an anti-microbial agent, a chemotherapeutic agent, an immuno-oncologic (10) agent, an immune-apoptosis inducing agent, an anti-diarrheal agent, an anti-histamine, a probiotic, a vitamin, a colorant, a buffer, an emulsifier, a sunscreen, a moisturizer, an analgesic agent, an anti-depressant agent, a skin nutrient, a medicinal herbal extract, a flavor, a flower essence, a protein, a lubricant, a buffering agent, a bulking agent and mixtures thereof.

9. The composition of any one of claims 1-8, wherein the at least one cannabinoid is selected from CBD, its isomers, derivatives and mixtures thereof.

10. The composition of any one of claims 1-9, wherein the at least one cannabinoid is selected from THC, its isomers, derivatives and mixtures thereof.

11. A dosage form formulated for oral, topical, parenteral, sublingual, buccal, rectal, intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, intrapleural, intratracheal, subcutaneous, transdermal, intradermal, or intranasal administration, or for inhalation, preferably for oral or sublingual administration to a patient in need thereof, comprising a therapeutically effective amount of a composition of any one of claims 1-10, for use in treatment, alleviation, or prevention of a disease, disorder or medical condition.

12. A kit comprising two pharmaceutical dosage forms of claim 11 and instructions for use, the first dosage form comprising a therapeutically effective amount of punicalagin and a carrier, and the second dosage form comprising a therapeutically effective amount of at least one cannabinoid and a carrier, for concomitant or sequential administration in either order to a subject in need thereof, for use in treatment, alleviation, or prevention of a disease, disorder or medical condition.

13. A method of treatment, prevention or amelioration of a disease, disorder or medical condition, comprising the administration to a subject in need thereof of a therapeutically effective amount of any one of the compositions of claims 1-10 or a dosage form of any one of claims 11-12, thereby treating, preventing or ameliorating the disease, disorder or medical condition.

14. The method according to claim 13, wherein the disease, disorder or medical condition is selected from a cardiovascular disease, atherosclerosis, blood vessel calcification, cerebral infarction, a gastro-enterologic disease, an autoimmune disease, an immunodeficiency disease, a neurodegenerative disease, neuronal damage, neuro-inflammation, an oncologic disease, a mental or psychiatric disease, a skin disease, a microbial, viral, bacterial or fungal infection, a blood vessels disease, cancer, hepatitis, hepatoma, headaches, fever, cough, cold, inflammation, allergy, vertigo, body aches, digestion disorders, obesity, sepsis, depression, glaucoma, pain, malaria, addiction, anxiety, depression, water retention, diarrhea, blood vessel dilation, nausea, appetite loss and pain associated with cancer and chemotherapy, nausea, appetite loss, pain and wasting associated with AIDS, toothache, arthritis, rheumatism, glaucoma, migraine, scurvy, muscle spasticity, alcohol and narcotics withdrawal, stress, asthma, Tourette syndrome, cervical dystonia, epileptic seizures, dementia, dysmenorrhea, diabetes, diabetes-related retinopathy, neuropathic pain, chronic pain, psoriasis, dermatitis, swimmer’s eczema, Alzheimer’s disease, Huntington disease, Parkinson’s disease, Lyme disease edema, liver inflammation, schizophrenia, colitis, painful spasms, fibromyalgia, sexual disfunction, post-traumatic stress disorder (PTSD), sepsis, necrotizing soft tissue infections (NSTI), acute or chronic pancreatitis, inflammatory bowel disease (IBD), non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS).

15. The method of claim 13, wherein the disease, disorder or medical condition is atherosclerosis and said method is beneficial for reducing inflammation in atherosclerotic plaques, thus rendering them less vulnerable to erupt and clog small blood vessels in the heart or brain.

16. The method of claim 13, wherein the disease, disorder or medical condition is atherosclerosis or blood vessel calcification and said method is beneficial for reducing Reactive Oxygen Species (ROS) presence and reactive oxidative stress in atherosclerotic lesions, thus preventing further damage to vessel tissue and accumulation of debris, calcium, inflammatory agents and cells in lesions.

17. The method of claim 13, wherein the disease, disorder or medical condition is cerebral infarction or stroke and said method is beneficial in reducing infarct size and increasing blood flow.

18. The method of claim 13, wherein the disease, disorder or medical condition is caused by inflammation or an inflammatory process and is selected from Alzheimer's disease, ankylosing spondylitis, arthritis (osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis, asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus erythematosus (SLE), nephritis, Parkinson's disease and ulcerative colitis.

19. The method of claim 13, wherein the disease, disorder or medical condition is caused by inflammation or an inflammatory process caused by the pro-inflammatory cytokine IL-6 and is selected from atherosclerosis, rheumatoid arthritis, systemic juvenile idiopathic arthritis, Castleman’s disease, neuromyelitis optica, giant cell arteritis and cytokine release syndrome.

20. The method of claim 13, wherein the disease, disorder or medical condition is selected from myocardial, liver or renal ischemic / reperfusion injury and the method is beneficial by providing protection.

21. The method according to any one of claims 13-20, wherein co-administration of therapeutically effective amounts of at least one cannabinoid and punicalagin results in a therapeutic effect selected from a synergistic effect, an additive effect, a potentiating effect and any combination thereof.

22. The method of any one of claims 13-21 , wherein the composition comprising at least one cannabinoid and punicalagin exhibits a synergistic therapeutic effect when compared to the therapeutic effect of the at least one cannabinoid and of punicalagin respectively administered to a patient in need thereof separately in a similar amount.

23. The method according to any one of claims 13-22 for treating, preventing or alleviating a disease, disorder or medical condition, comprising administering concomitantly or sequentially in either order the two dosage forms of the kit of claim 12.

24. An article of manufacture comprising any one of the compositions of claims 1-10, wherein in the form of a cosmeceutical, a nu tricosmetic, a body care product, a personal hygiene product or a cosmetic product selected from a body lotion, a soap, a body wash, a moisturizer, a self-tanner, a hand cream, a body scmb, a sunscreen, a bath product, a toothpaste, a soap, a shampoo, a mouthwash, a deodorant, an antiperspirant, a shaving soap, an anti-wrinkle product, a moisturizing cream, a face mask, a makeup and a lipstick.